Blood sample collection tube

ABSTRACT

A blood sample collection tube and other vessels are described including an article surface and a coating set comprising a tie coating or layer of SiOxCy or SiNxCy applied to the article surface, a barrier coating or layer of SiOx, and a pH protective layer of SiOxCy or SiNxCy. The vessels optionally contain a fluid with a pH of 4 to 8, alternatively 5 to 9. The barrier coating or layer prevents oxygen from penetrating into the thermoplastic vessel, and the tie coating or layer and pH protective coating or layer together protect the barrier layer from the contents of the vessel.

This application is a continuation-in-part of U.S. Ser. No. 16/029,923,filed Jul. 9, 2018, now pending, which is a continuation of U.S. Ser.No. 15/385,150, filed Dec. 20, 2016, now U.S. patent Ser. No.10/016,338, which is a continuation of U.S. Ser. No. 14/205,329, filedMar. 11, 2014, now U.S. Pat. No. 9,554,968, which claims the priority ofU.S. Provisional Applications 61/776,733, filed Mar. 11, 2013, and61/800,746, filed Mar. 15, 2013. This application is also acontinuation-in-part of U.S. Ser. No. 14/357,418, filed Nov. 9, 2012,now U.S. patent Ser. No. 10/189,603, which is the U.S. National Stage ofInternational Application No. PCT/US2012/064489, which claims priorityto U.S. Ser. No. 61/645,003, filed May 9, 2012, U.S. Ser. No.61/636,377, filed Apr. 20, 2012, and U.S. Ser. No. 61/558,885, filedNov. 11, 2011. The entire specification and all the drawings of eachapplication mentioned in this paragraph is incorporated here byreference to provide continuity of disclosure.

The specification and drawings of U.S. Ser. No. 12/779,007, filed May12, 2010, now U.S. Pat. No. 7,985,188, is also incorporated here byreference in its entirety.

FIELD

The present invention relates to the technical field of thermoplasticblood collection vessels, for example such vessels in which bloodsamples are collected and transported to a medical laboratory fortesting.

BACKGROUND

Blood sample collection vessels, commonly tubes, are used for drawingblood from a patient for medical analysis. The tubes are commonly soldstoppered and evacuated. The patient's blood is communicated to theinterior of a tube by inserting one end of a double-ended hypodermicneedle into the patient's blood vessel and impaling the closure of theevacuated blood collection tube on the other end of the double-endedneedle. The vacuum in the evacuated blood collection tube draws theblood (or more precisely, the blood pressure of the patient pushes theblood) through the needle into the evacuated blood collection tube,increasing the pressure within the tube and thus decreasing the pressuredifference causing the blood to flow. The blood flow typically continuesuntil the tube is removed from the needle or the pressure difference istoo small to support flow.

Evacuated blood collection tubes should have a substantial shelf life tofacilitate efficient and convenient distribution and storage of thetubes prior to use. For example, a one-year shelf life is desirable, andprogressively longer shelf lives, such as 18 months, 24 months, or 36months, are also desired in some instances. The tube desirably remainsessentially fully evacuated, at least to the degree necessary to drawenough blood for analysis (a common standard is that the tube retains atleast 90% of the original draw volume), for the full shelf life, withvery few (optimally no) defective tubes being provided.

A tube having a lower-than-standard vacuum level at the time of use islikely to cause the phlebotomist using the tube to fail to drawsufficient blood. The phlebotomist might then need to obtain and use oneor more additional tubes to obtain an adequate blood sample.

To meet this shelf-life requirement, evacuated blood collection tubeshave typically been made of glass. Glass vessels have been favoredbecause glass is more gas tight and inert to pre-filled contents thanuntreated plastics. Also, due to its traditional use, glass is wellaccepted, as it is known to be relatively innocuous when contacted withblood or other medical samples.

Glass vessels, however, have several serious disadvantages when used asblood tubes. They can break, and if broken form sharp shards fromremnants of the vessel that can injure workers or patients, both due tothe direct effects of laceration and by transmitting infections vialacerated skin. Breakage after a sample is collected can also cause thesample to be compromised or lost. Glass vessels also are expensive tomanufacture, as glass cannot be injection molded.

Thermoplastic blood collection tubes have been developed to overcome thedisadvantages of glass vessels. Plastic vessels are rarely broken innormal use, and if broken do not form sharp shards from remnants of thevessel, like a glass tube would. As-molded thermoplastic bloodcollection tubes previously have not had gas barrier properties adequateto provide a commercially desirable shelf life when used as evacuatedblood collection tubes. Plastic has allowed small molecule gases topermeate into (or out of) the article. The permeability of plastics togases has been significantly greater than that of glass. Many plasticshave allowed water vapor to pass through articles to a greater degreethan glass. Some plastic vessels contain organic or inorganic metalcompounds in the plastic that can leach out or be extracted into thesample vessel.

U.S. Pat. No. 7,985,188 discloses barrier-coated thermoplastic bloodcollection tubes including a barrier coating or layer applied byplasma-enhanced chemical vapor deposition (PECVD) to improve their gasbarrier and leaching properties. An example of a suitable barriercoating disclosed by U.S. Pat. No. 7,985,188 is SiO_(x), in which x inthis formula is from about 1.5 to about 2.9 as characterized by x-rayphotoelectron spectroscopy (XPS).

Some blood collection tubes, as sold, contain an aqueous reagent, forexample EDTA, heparin or sodium citrate, to preserve the blood betweenthe times of collection and analysis. Some such reagents can attack anddissolve the barrier coating over time, leading to increased permeationof external atmospheric gas, reduction in the vacuum level, and thus ashorter shelf life of the barrier-coated thermoplastic evacuated bloodcollection tubes.

Since many of these blood collection vessels are inexpensive and used inlarge quantities, for certain applications it will be useful to reliablyobtain the necessary shelf life without increasing the manufacturingcost to a prohibitive level.

Thus, there is a desire for plastic pharmaceutical packages or othervessels, in particular plastic vessels, with gas and solute barrierproperties which approach the properties of glass without undulyincreasing the manufacturing cost.

SUMMARY

A first embodiment is a blood sample collection tube comprising a walland a coating set on the surface. The wall has an interior surfacecomprising a cyclic olefin polymer (COP) or a cyclic olefin copolymer(COC). The coating set on the surface comprises a tie coating or layer,a barrier coating or layer, and a pH protective coating or layer.

In this first embodiment, the tie coating or layer comprisesSiO_(x)C_(y) or SiN_(x)C_(y) wherein x is from about 0.5 to about 2.4and y is from about 0.6 to about 3. The tie coating or layer has anouter surface facing the wall surface, and the tie coating or layer hasan interior surface.

In this first embodiment, the barrier coating or layer comprisesSiO_(x), wherein x is from 1.5 to 2.9, and is from 2 to 1000 nm thick.The barrier coating or layer of SiO_(x) has an outer surface facing theinterior surface of the tie coating or layer, and the barrier coating orlayer of SiO_(x) has an interior surface. The barrier coating or layeris effective to reduce the ingress of atmospheric gas through the wallcompared to an uncoated wall.

In this first embodiment, the pH protective coating or layer comprisesSiO_(x)C_(y) or SiN_(x)C_(y) wherein x is from about 0.5 to about 2.4and y is from about 0.6 to about 3. The pH protective coating or layercan be formed on the barrier coating or layer. The pH protective coatingor layer is formed by chemical vapor deposition of a precursor selectedfrom an acyclic siloxane, a monocyclic siloxane, a polycyclic siloxane,a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, apolysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, anazasilatrane, an azasilquasiatrane, an azasilproatrane, or a combinationof any two or more of these precursors.

In this first embodiment, the rate of erosion of the pH protectivecoating or layer, if directly contacted by a fluid composition having apH at some point between 5 and 9, is less than the rate of erosion ofthe barrier coating or layer, if directly contacted by the fluidcomposition.

A second embodiment is a blood sample collection tube comprising avessel having a lumen defined at least in part by a wall. The wall hasan interior surface comprising a cyclic olefin polymer (COP) or a cyclicolefin copolymer (COC) facing the lumen, and the wall has an outersurface. A coating set on the interior surface comprises a tie coatingor layer, a barrier coating or layer, and a pH protective coating orlayer.

In this second embodiment, the tie coating or layer comprisesSiO_(x)C_(y) or SiN_(x)C_(y) wherein x is from about 0.5 to about 2.4and y is from about 0.6 to about 3. The tie coating or layer has aninterior surface facing the lumen and an outer surface facing the wallinterior surface.

In this second embodiment, the barrier coating or layer comprisesSiO_(x), wherein x is from 1.5 to 2.9, from 2 to 1000 nm thick. Thebarrier coating or layer of SiO_(x) has an interior surface facing thelumen and an outer surface facing the interior surface of the tiecoating or layer. The barrier coating or layer is effective to reducethe ingress of atmospheric gas into the lumen compared to an vesselwithout a barrier coating or layer.

In this second embodiment, the pH protective coating or layer comprisesSiO_(x)C_(y) or SiN_(x)C_(y) wherein x is from about 0.5 to about 2.4and y is from about 0.6 to about 3. The pH protective coating or layerhas an interior surface facing the lumen and an outer surface facing theinterior surface of the barrier coating or layer.

In this second embodiment, the combination of the tie coating or layerand the pH protective coating or layer is effective to increase thecalculated shelf life of the package (total Si/Si dissolution rate).

In this second embodiment, a fluid composition is contained in the lumenand has a pH between 5 and 9.

In this second embodiment, the calculated shelf life of the package ismore than six months at a storage temperature of 4° C.

A third embodiment is a blood sample collection tube comprising athermoplastic wall, a fluid composition, a tie coating or layer, abarrier coating or layer, and a pH protective coating or layer.

In this third embodiment, the thermoplastic wall has an interior surfacecomprising a cyclic olefin polymer (COP) or a cyclic olefin copolymer(COC) and encloses a lumen.

In this third embodiment, the fluid composition contained in the lumenhas a pH greater than 5 and is disposed in the lumen.

In this third embodiment, the tie coating or layer comprisesSiO_(x)C_(y) or SiN_(x)C_(y) wherein x is from about 0.5 to about 2.4and y is from about 0.6 to about 3. The tie coating or layer has anouter surface facing the wall surface, and the tie coating or layer hasan interior surface.

In this third embodiment, in the barrier coating or layer of SiO_(x), xis between 1.5 and 2.9. The barrier coating or layer is applied byplasma-enhanced chemical vapor deposition (PECVD). The barrier coatingor layer is positioned between the interior surface of the tie coatingor layer and the fluid composition, and the barrier coating or layer issupported by the thermoplastic wall. The barrier coating or layer hasthe characteristic of being subject to being measurably diminished inbarrier improvement factor in less than six months as a result of attackby the fluid composition.

In this third embodiment, in the pH protective coating or layer ofSiO_(x)C_(y), x is between 0.5 and 2.4 and y is between 0.6 and 3. ThepH protective coating or layer is applied by PECVD, and the pHprotective coating or layer is positioned between the barrier coating orlayer and the fluid composition and supported by the thermoplastic wall.The pH protective coating or layer and the tie coating or layer togetherare effective to keep the barrier coating or layer at leastsubstantially undissolved as a result of attack by the fluid compositionfor a period of at least six months.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a plastic vessel of any type provided with a trilayercoating according to any embodiment.

FIG. 2 is a detail view of the plastic vessel of FIG. 1.

FIG. 3 corresponds to FIG. 23 of U.S. Pat. No. 7,985,188 and shows avessel 268 configured as an evacuated blood collection tube according toany embodiment. In FIG. 3 the closure 270 is an assembly of a stopperand a shield with the vessel 268.

FIG. 4 is a plot of silicon dissolution versus exposure time at pH 6 fora glass container versus a plastic container having an SiO_(x) barrierlayer coated in the inside wall according to any embodiment.

FIG. 5 is a plot of silicon dissolution versus exposure time at pH 7 fora glass container versus a plastic container having an SiO_(x) barrierlayer coated in the inside wall according to any embodiment.

FIG. 6 is a plot of silicon dissolution versus exposure time at pH 8 fora glass container versus a plastic container having an SiO_(x) barrierlayer coated in the inside wall according to any embodiment.

FIG. 7 is a plot of the SiO_(x) coating thickness necessary initially toleave a 30 nm residual coating thickness when stored with solutions atdifferent nominal pH values from 3 to 9 according to any embodiment.

FIG. 8 shows the silicon dissolution rates at pH 8 and 40° C. of variousPECVD coatings according to any embodiment.

FIG. 9 is a plot of the ratio of Si—O—Si symmetric/asymmetric stretchingmode versus energy input per unit mass (W/FM or KJ/kg) of a PECVDcoating using as the reactive precursor gases OMCTS and oxygen accordingto any embodiment.

FIG. 10 is a plot of silicon shelf life (days) versus energy input perunit mass (W/FM or KJ/kg) of a PECVD coating using as the reactiveprecursor gases OMCTS and oxygen. according to any embodiment

FIG. 11 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating according to any embodiment.

FIG. 12 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating according to any embodiment.

FIG. 13 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating according to any embodiment.

FIG. 14 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating according to any embodiment.

FIG. 15 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating, originally presented as FIG. 5of U.S. Pat. No. 8,067,070, annotated to show the calculation of theO-Parameter referred to in that patent, according to any embodiment.

FIG. 16 is a schematic view of a syringe with a trilayer coatingaccording to FIGS. 1, 2, and 3, showing a cylindrical region andspecific points where data was taken, according to any embodiment.

FIG. 17 is a Trimetric map of the overall trilayer coating thicknessversus position in the cylindrical region of a syringe illustrated byFIGS. 16, 1, and 2, representing a vessel according to any embodiment.

FIG. 18 is a photomicrograhic sectional view showing the substrate andcoatings of the trilayer coating at position 2 shown in FIG. 16,according to any embodiment.

FIG. 19 is another Trimetric map of the overall trilayer coatingthickness versus position in the cylindrical region of a vesselillustrated by FIGS. 16, 1, and 2, according to any embodiment.

FIG. 20 is a plot of coating thickness, representing the same coating asFIG. 19, at Positions 1, 2, 3, and 4 shown in FIG. 16, according to anyembodiment.

FIG. 21 is a schematic illustration of a vessel, showing points on itssurface where measurements were made in a working example, according toany embodiment.

FIG. 22 is a photograph showing the benefit of the present trilayercoating in preventing pinholes after attack by an alkaline reagent, asdiscussed in the working examples, according to any embodiment.

FIG. 22A is an enlarged detail view of the indicated portion of FIG. 22,according to any embodiment.

FIG. 23 is a view similar to FIG. 3 showing a vessel 268 configured asan evacuated blood collection tube according to any embodimentcontaining a fluid 218.

The following reference characters are used in the drawing figuresaccording to any embodiment:

210 Pharmaceutical package 212 Lumen 214 Wall 218 Fluid 268 Vessel 270Closure 274 Lumen 285 Vessel coating or layer set 285a Closure coatingor layer set (inner surface) 285b Closure coating or layer set (sidesurface) 286 pH protective coating or layer 288 Barrier layer 289 Tiecoating or layer

In the context of the present invention, the following definitions andabbreviations are used:

The word “comprising” according to any embodiment does not exclude otherelements or steps, and the indefinite article “a” or “an” does notexclude a plurality unless indicated otherwise. Whenever a parameterrange is indicated, it is intended to disclose the parameter valuesgiven as limits of the range and all values of the parameter fallingwithin said range.

“First” and “second” or similar references to, for example, deposits ofcoatings or layers, processing stations or processing devices accordingto any embodiment refer to the minimum number of deposits, processingstations or devices that are present, but do not necessarily representthe order or total number of deposits, processing stations and devicesor require additional deposits, processing stations and devices beyondthe stated number. These terms do not limit the number of processingstations or the particular processing carried out at the respectivestations. For example, a “first” deposit in the context of thisspecification can be either the only deposit or any one of pluraldeposits, without limitation. In other words, recitation of a “first”deposit allows but does not require an embodiment that also has a secondor further deposit.

For purposes of the present invention according to any embodiment, an“organosilicon precursor” is a compound having at least one of thelinkages:

which is a tetravalent silicon atom connected to an oxygen or nitrogenatom and an organic carbon atom (an organic carbon atom being a carbonatom bonded to at least one hydrogen atom). A volatile organosiliconprecursor, defined as such a precursor that can be supplied as a vaporin a PECVD apparatus, is an optional organosilicon precursor.Optionally, the organosilicon precursor is a linear siloxane or amonocyclic siloxane, or a combination of any two or more of theseprecursors.

A “vessel” in the context of the present invention can be any type ofvessel with at least one opening and a wall defining an inner orinterior surface, according to any embodiment. The substrate can be thewall of a vessel having a lumen, according to any embodiment.

The term “at least” in the context of the present invention according toany embodiment means “equal or more” than the integer following theterm. Thus, a vessel in the context of the present invention has one ormore openings. One or two openings, like the openings of a sample tube(one opening) or a vessel (two openings) are preferred. A vesselaccording to the present invention can be a sample tube, for example forcollecting or storing biological fluids like blood according to anyembodiment.

A vessel according to any embodiment can be of any shape, a vesselhaving a substantially cylindrical wall adjacent to at least one of itsopen ends being preferred. Generally, the interior wall of the vessel iscylindrically shaped, like, for example in a sample tube. Sample tubesare contemplated, according to any embodiment.

The values of w, x, y, and z according to any embodiment are applicableto the empirical composition Si_(w)O_(x)C_(y)H_(z) throughout thisspecification. The values of w, x, y, and z used throughout thisspecification should be understood as ratios or an empirical formula(for example for a coating or layer), rather than as a limit on thenumber or type of atoms in a molecule. For example,octamethylcyclotetrasiloxane, which has the molecular compositionSi₄O₄C₈H₂₄, can be described by the following empirical formula, arrivedat by dividing each of w, x, y, and z in the molecular formula by 4, thelargest common factor: Si₁O₁C₂H₆. The values of w, x, y, and z are alsonot limited to integers according to any embodiment. For example,(acyclic) octamethyltrisiloxane, molecular composition Si₃O₂C₈H₂₄, isreducible to Si₁O_(0.67)C_(2.67)H₈. Also, although SiO_(x)C_(y)H_(z) isdescribed as equivalent to SiO_(x)C_(y) according to any embodiment, itis not necessary to show the presence of hydrogen in any proportion toshow the presence of SiO_(x)C_(y).

The atomic ratio according to any embodiment can be determined by XPS.Taking into account the H atoms, which are not measured by XPS, thecoating or layer may thus in one aspect have the formulaSi_(w)O_(x)C_(y)H_(z) (or its equivalent SiO_(x)C_(y)), for examplewhere w is 1, x is from about 0.5 to about 2.4, y is from about 0.6 toabout 3, and z is from about 2 to about 9.

DETAILED DESCRIPTION

The present invention will now be described more fully, with referenceto the accompanying drawings, according to any embodiment. Thisinvention can, however, be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth here. Rather,these embodiments are examples, which has the full scope indicated bythe language of the claims. Like numbers refer to like or correspondingelements throughout. The following disclosure relates to all embodimentsunless specifically limited to a certain embodiment.

Vessels and Coating Sets

Every embodiment, illustrated most broadly by FIGS. 1 and 2, is a vessel210 including a wall 214 enclosing a lumen 212 and a vessel coating orlayer set 285 on at least a portion of the wall 214 facing the lumen212. FIG. 1 shows a vessel having at least a single opening; vesselshaving two openings or more than two openings are also contemplated inany embodiment.

The vessel 210 in any embodiment may also include a closure as showngenerically in FIG. 1. Several examples of the closure of FIG. 1 are astopper, septum, or the like.

The vessel in any embodiment is made of a thermoplastic material, forexample cyclic olefin polymer (COP) or cyclic olefin copolymer (COC).

An embodiment of the vessel coating or layer set 285, 285 a, or 285 b inany embodiment is at least one tie coating or layer 289, at least onebarrier coating or layer 288, and at least one pH protective coating orlayer 286, illustrated in FIGS. 1-2 and present in any embodiment. Thisvessel coating or layer set is sometimes known as a “trilayer coating”in which the barrier coating or layer 288 of SiO_(x) is protectedagainst contents having a pH otherwise high enough to remove it by beingsandwiched between the pH protective coating or layer 286 and the tiecoating or layer 289, each an organic layer of SiO_(x)C_(y) as definedin this specification. Specific examples of this trilayer coating in anyembodiment are provided in this specification. The contemplatedthicknesses of the respective layers in nm (preferred ranges inparentheses) are given in the Trilayer Thickness Table.

Trilayer Thickness Table Adhesion Barrier Protection  5-100  20-200 50-500 (5-20) (20-30) (100-200)

The trilayer coating set 285 includes as a first layer an adhesion ortie coating or layer 289 that improves adhesion of the barrier coatingor layer to the COP substrate. The adhesion or tie coating or layer 289is also believed to relieve stress on the barrier coating or layer 288,making the barrier layer less subject to damage from thermal expansionor contraction or mechanical shock. The adhesion or tie coating or layer289 is also believed to decouple defects between the barrier coating orlayer 288 and the COP substrate. This is believed to occur because anypinholes or other defects that may be formed when the adhesion or tiecoating or layer 289 is applied tend not to be continued when thebarrier coating or layer 288 is applied, so the pinholes or otherdefects in one coating do not line up with defects in the other. Theadhesion or tie coating or layer 289 has some efficacy as a barrierlayer, so even a defect providing a leakage path extending through thebarrier coating or layer 289 is blocked by the adhesion or tie coatingor layer 289.

The trilayer coating set 285 includes as a second layer a barriercoating or layer 288 that provides a barrier to oxygen that haspermeated the COP wall. The barrier coating or layer 288 also is abarrier to extraction of the composition of the vessel wall 214 by thecontents of the lumen 214.

The trilayer coating set 285 includes as a third layer a pH protectivecoating or layer 286 that provides protection of the underlying barriercoating or layer 288 against contents of the vessel, including where asurfactant is present.

The features of each layer of the trilayer coating set are furtherdescribed below.

Tie Coating or Layer

The tie coating or layer 289 has at least two functions. One function ofthe tie coating or layer 289 is to improve adhesion of a barrier coatingor layer 288 to a substrate, in particular a thermoplastic substrate.For example, a tie coating or layer, also referred to as an adhesionlayer or coating can be applied to the substrate and the barrier layercan be applied to the adhesion layer to improve adhesion of the barrierlayer or coating to the substrate.

Another function of the tie coating or layer 289 has been discovered: atie coating or layer 289 applied under a barrier coating or layer 288can improve the function of a pH protective coating or layer 286 appliedover the barrier coating or layer 288.

The tie coating or layer 289 can be composed of, comprise, or consistessentially of SiO_(x)C_(y), in which x is between 0.5 and 2.4 and y isbetween 0.6 and 3. Alternatively, the atomic ratio can be expressed asthe formula Si_(w)O_(x)C_(y), The atomic ratios of Si, O, and C in thetie coating or layer 289 are, as several options:

-   -   Si 100: O 50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2);    -   Si 100: O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to 2)    -   Si 100: O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9 to        1.5)    -   Si 100: O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to        1.4), or    -   Si 100: O 92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to        1.33)

The atomic ratio can be determined by XPS. Taking into account the Hatoms, which are not measured by XPS, the tie coating or layer 289 maythus in one aspect have the formula Si_(w)O_(x)C_(y)H_(z) (or itsequivalent SiO_(x)C_(y)), for example where w is 1, x is from about 0.5to about 2.4, y is from about 0.6 to about 3, and z is from about 2 toabout 9. Typically, tie coating or layer 289 would hence contain 36% to41% carbon normalized to 100% carbon plus oxygen plus silicon.

Optionally, the tie coating or layer can be similar or identical incomposition with the pH protective coating or layer 286 describedelsewhere in this specification, although this is not a requirement.

The tie coating or layer 289 is contemplated generally to be from 5 nmto 100 nm thick, preferably from 5 to 20 nm thick, particularly ifapplied by chemical vapor deposition. These thicknesses are notcritical. Commonly but not necessarily, the tie coating or layer 289will be relatively thin, since its function is to change the surfaceproperties of the substrate.

Barrier Layer

A barrier coating or layer 288 optionally can be deposited by plasmaenhanced chemical vapor deposition (PECVD) or other chemical vapordeposition processes on the vessel of a pharmaceutical package, inparticular a thermoplastic package, to prevent oxygen, carbon dioxide,or other gases from entering the vessel and/or to prevent leaching ofthe pharmaceutical material into or through the package wall.

The barrier coating or layer for any embodiment defined in thisspecification (unless otherwise specified in a particular instance) is acoating or layer, optionally applied by PECVD as indicated in U.S. Pat.No. 7,985,188. The barrier layer optionally is characterized as an“SiO_(x)” coating, and contains silicon, oxygen, and optionally otherelements, in which x, the ratio of oxygen to silicon atoms, is fromabout 1.5 to about 2.9, or 1.5 to about 2.6, or about 2. Thesealternative definitions of x apply to any use of the term SiO_(x) inthis specification. The barrier coating or layer is applied, for exampleto the interior of a pharmaceutical package or other vessel, for examplea sample collection tube or another type of vessel.

The barrier coating 288 comprises or consists essentially of SiO_(x),wherein x is from 1.5 to 2.9, from 2 to 1000 nm thick, the barriercoating 288 of SiO_(x) having an interior surface 220 facing the lumen212 and an outer surface 222 facing the wall 214 article surface 254,the barrier coating 288 being effective to reduce the ingress ofatmospheric gas into the lumen 212 compared to an uncoated vessel 250.One suitable barrier composition is one where x is 2.3, for example. Forexample, the barrier coating or layer such as 288 of any embodiment canbe applied at a thickness of at least 2 nm, or at least 4 nm, or atleast 7 nm, or at least 10 nm, or at least 20 nm, or at least 30 nm, orat least 40 nm, or at least 50 nm, or at least 100 nm, or at least 150nm, or at least 200 nm, or at least 300 nm, or at least 400 nm, or atleast 500 nm, or at least 600 nm, or at least 700 nm, or at least 800nm, or at least 900 nm. The barrier coating or layer can be up to 1000nm, or at most 900 nm, or at most 800 nm, or at most 700 nm, or at most600 nm, or at most 500 nm, or at most 400 nm, or at most 300 nm, or atmost 200 nm, or at most 100 nm, or at most 90 nm, or at most 80 nm, orat most 70 nm, or at most 60 nm, or at most 50 nm, or at most 40 nm, orat most 30 nm, or at most 20 nm, or at most 10 nm, or at most 5 nmthick. Ranges of 20-200 nm, optionally 20-30 nm, are contemplated.Specific thickness ranges composed of any one of the minimum thicknessesexpressed above, plus any equal or greater one of the maximumthicknesses expressed above, are expressly contemplated.

The thickness of the SiO_(x) or other barrier coating or layer can bemeasured, for example, by transmission electron microscopy (TEM), andits composition can be measured by X-ray photoelectron spectroscopy(XPS). The pH protective coating or layer described herein can beapplied to a variety of pharmaceutical packages or other vessels madefrom plastic or glass, for example to plastic tubes, vessels, andsyringes.

A barrier coating or layer 286 of SiO_(x), in which x is between 1.5 and2.9, is applied by plasma enhanced chemical vapor deposition (PECVD)directly or indirectly to the thermoplastic wall 214 (for example a tiecoating or layer 289 can be interposed between them) so that in thefilled pharmaceutical package or other vessel 210 the barrier coating orlayer 286 is located between the inner or interior surface 220 of thethermoplastic wall 214 and the fluid 218.

The barrier coating or layer 286 of SiO_(x) is supported by thethermoplastic wall 214. The barrier coating or layer 286 as describedelsewhere in this specification, or in U.S. Pat. No. 7,985,188, can beused in any embodiment.

Certain barrier coatings or layers 286 such as SiOx as defined here havebeen found to have the characteristic of being subject to beingmeasurably diminished in barrier improvement factor in less than sixmonths as a result of attack by certain relatively high pH contents ofthe coated vessel as described elsewhere in this specification,particularly where the barrier coating or layer directly contacts thecontents. This issue can be addressed using a pH protective coating orlayer as discussed in this specification.

pH Protective Coating or Layer

The inventors have found that barrier layers or coatings of SiO_(x) areeroded or dissolved by some fluids, for example aqueous compositionshaving a pH above about 5. Since coatings applied by chemical vapordeposition can be very thin—tens to hundreds of nanometers thick—even arelatively slow rate of erosion can remove or reduce the effectivenessof the barrier layer in less time than the desired shelf life of aproduct package. This is particularly a problem for fluid pharmaceuticalcompositions, since many of them have a pH of roughly 7, or more broadlyin the range of 5 to 9, similar to the pH of blood and other human oranimal fluids. The higher the pH of the pharmaceutical preparation, themore quickly it erodes or dissolves the SiO_(x) coating. Optionally,this problem can be addressed by protecting the barrier coating or layer288, or other pH sensitive material, with a pH protective coating orlayer 286.

Optionally, the pH protective coating or layer 286 can be composed of,comprise, or consist essentially of Si_(w)O_(x)C_(y)H_(z) (or itsequivalent SiO_(x)C_(y)) or Si_(w)N_(x)C_(y)H_(z) or its equivalentSiN_(x)C_(y)), each as defined previously. The atomic ratio of Si:O:C orSi:N:C can be determined by XPS (X-ray photoelectron spectroscopy).Taking into account the H atoms, the pH protective coating or layer maythus in one aspect have the formula Si_(w)O_(x)C_(y)H_(z), or itsequivalent SiO_(x)C_(y), for example where w is 1, x is from about 0.5to about 2.4, y is from about 0.6 to about 3, and z is from about 2 toabout 9.

Typically, expressed as the formula Si_(w)O_(x)C_(y), the atomic ratiosof Si, O, and C are, as several options:

-   -   Si 100: O 50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2);    -   Si 100: O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to 2)    -   Si 100: O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9 to        1.5)    -   Si 100: O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to        1.4)    -   Si 100: O 92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to        1.33), or    -   Si 100: O 80-130: C 90-150.

Alternatively, the pH protective coating or layer can have atomicconcentrations normalized to 100% carbon, oxygen, and silicon, asdetermined by X-ray photoelectron spectroscopy (XPS) of less than 50%carbon and more than 25% silicon. Alternatively, the atomicconcentrations are from 25 to 45% carbon, 25 to 65% silicon, and 10 to35% oxygen. Alternatively, the atomic concentrations are from 30 to 40%carbon, 32 to 52% silicon, and 20 to 27% oxygen. Alternatively, theatomic concentrations are from 33 to 37% carbon, 37 to 47% silicon, and22 to 26% oxygen.

The thickness of the pH protective coating or layer can be, for example:

-   -   from 10 nm to 1000 nm;    -   alternatively from 10 nm to 1000 nm;    -   alternatively from 10 nm to 900 nm;    -   alternatively from 10 nm to 800 nm;    -   alternatively from 10 nm to 700 nm;    -   alternatively from 10 nm to 600 nm;    -   alternatively from 10 nm to 500 nm;    -   alternatively from 10 nm to 400 nm;    -   alternatively from 10 nm to 300 nm;    -   alternatively from 10 nm to 200 nm;    -   alternatively from 10 nm to 100 nm;    -   alternatively from 10 nm to 50 nm;    -   alternatively from 20 nm to 1000 nm;    -   alternatively from 50 nm to 1000 nm;    -   alternatively from 10 nm to 1000 nm;    -   alternatively from 50 nm to 800 nm;    -   alternatively from 100 nm to 700 nm;    -   alternatively from 300 to 600 nm.

Optionally, the atomic concentration of carbon in the protective layer,normalized to 100% of carbon, oxygen, and silicon, as determined byX-ray photoelectron spectroscopy (XPS), can be greater than the atomicconcentration of carbon in the atomic formula for the organosiliconprecursor. For example, embodiments are contemplated in which the atomicconcentration of carbon increases by from 1 to 80 atomic percent,alternatively from 10 to 70 atomic percent, alternatively from 20 to 60atomic percent, alternatively from 30 to 50 atomic percent,alternatively from 35 to 45 atomic percent, alternatively from 37 to 41atomic percent.

Optionally, the atomic ratio of carbon to oxygen in the pH protectivecoating or layer can be increased in comparison to the organosiliconprecursor, and/or the atomic ratio of oxygen to silicon can be decreasedin comparison to the organosilicon precursor.

Optionally, the pH protective coating or layer can have an atomicconcentration of silicon, normalized to 100% of carbon, oxygen, andsilicon, as determined by X-ray photoelectron spectroscopy (XPS), lessthan the atomic concentration of silicon in the atomic formula for thefeed gas. For example, embodiments are contemplated in which the atomicconcentration of silicon decreases by from 1 to 80 atomic percent,alternatively by from 10 to 70 atomic percent, alternatively by from 20to 60 atomic percent, alternatively by from 30 to 55 atomic percent,alternatively by from 40 to 50 atomic percent, alternatively by from 42to 46 atomic percent.

As another option, a pH protective coating or layer is contemplated thatcan be characterized by a sum formula wherein the atomic ratio C:O canbe increased and/or the atomic ratio Si:O can be decreased in comparisonto the sum formula of the organosilicon precursor.

The pH protective coating or layer 286 commonly is located between thebarrier coating or layer 288 and the fluid 218 in the finished articlesuch as the pharmaceutical package 210 shown in FIG. 23. In thisinstance, the pharmaceutical package 210 is a blood sample collectiontube or other vessel 268, shown for example in FIG. 3, containing areagent or other fluid 218 as shown in FIG. 23, and evacuated tofacilitate its use for collecting an intravenous blood sample. Onenon-limiting example of a reagent is an aqueous sodium citrate reagent,which is suitable for preventing or reducing blood coagulation The pHprotective coating or layer 286 is supported by the thermoplastic wall214.

The pH protective coating or layer 286 optionally is effective to keepthe barrier coating or layer 288 at least substantially undissolved as aresult of attack by the fluid 218 for a period of at least six months.

The pH protective coating or layer can have a density between 1.25 and1.65 g/cm³, alternatively between 1.35 and 1.55 g/cm³, alternativelybetween 1.4 and 1.5 g/cm³, alternatively between 1.4 and 1.5 g/cm³,alternatively between 1.44 and 1.48 g/cm³, as determined by X-rayreflectivity (XRR). Optionally, the organosilicon compound can beoctamethylcyclotetrasiloxane and the pH protective coating or layer canhave a density which can be higher than the density of a pH protectivecoating or layer made from HMDSO as the organosilicon compound under thesame PECVD reaction conditions.

The pH protective coating or layer optionally can prevent or reduce theprecipitation of a compound or component of a composition in contactwith the pH protective coating or layer, in particular can prevent orreduce insulin precipitation or blood clotting, in comparison to theuncoated surface and/or to a barrier coated surface using HMDSO asprecursor.

The interior surface of the pH protective coating or layer optionallycan have a contact angle (with distilled water) of from 90° to 110°,optionally from 80° to 120°, optionally from 70° to 130°, as measured byGoniometer Angle measurement of a water droplet on the pH protectivesurface, per ASTM D7334-08 “Standard Practice for Surface Wettability ofCoatings, Substrates and Pigments by Advancing Contact AngleMeasurement.”

The passivation layer or pH protective coating or layer 286 optionallyshows an O-Parameter measured with attenuated total reflection (ATR) ofless than 0.4, measured as:

${O\text{-}{Parameter}} = \frac{{{Intensity}\mspace{14mu}{at}\mspace{14mu} 1253\mspace{14mu}{cm}} - 1}{{{Maximum}\mspace{14mu}{intensity}\mspace{14mu}{in}\mspace{14mu}{the}\mspace{14mu}{range}\mspace{14mu} 1000\mspace{14mu}{to}\mspace{14mu} 1100\mspace{14mu}{cm}} - 1}$

The O-Parameter is defined in U.S. Pat. No. 8,067,070, which claims anO-parameter value of most broadly from 0.4 to 0.9. It can be measuredfrom physical analysis of an FTIR amplitude versus wave number plot tofind the numerator and denominator of the above expression, as shown inFIG. 15, which is the same as FIG. 5 of U.S. Pat. No. 8,067,070, exceptannotated to show interpolation of the wave number and absorbance scalesto arrive at an absorbance at 1253 cm⁻¹ of 0.0424 and a maximumabsorbance at 1000 to 1100 cm⁻¹ of 0.08, resulting in a calculatedO-parameter of 0.53. The O-Parameter can also be measured from digitalwave number versus absorbance data.

U.S. Pat. No. 8,067,070 asserts that the claimed O-parameter rangeprovides a superior pH protective coating or layer, relying onexperiments only with HMDSO and HMDSN, which are both non-cyclicsiloxanes. Surprisingly, it has been found by the present inventors thatif the PECVD precursor is a cyclic siloxane, for example OMCTS,O-parameters outside the ranges claimed in U.S. Pat. No. 8,067,070,using OMCTS, provide even better results than are obtained in U.S. Pat.No. 8,067,070 with HMDSO.

Alternatively in any embodiment, the O-parameter has a value of from 0.1to 0.39, or from 0.15 to 0.37, or from 0.17 to 0.35.

Even another aspect is a composite material according to any embodiment,wherein the passivation layer shows an N-Parameter measured withattenuated total reflection (ATR) of less than 0.7, measured as:

${N\text{-}{Parameter}} = {\frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 840\mspace{14mu}{cm}^{- 1}}{{Intensity}\mspace{14mu}{at}\mspace{14mu} 799\mspace{14mu}{cm}^{- 1}}.}$

The N-Parameter is also described in U.S. Pat. No. 8,067,070, and ismeasured analogously to the O-Parameter except that intensities at twospecific wave numbers are used—neither of these wave numbers is a range.U.S. Pat. No. 8,067,070 claims a passivation layer with an N-Parameterof 0.7 to 1.6. Again, the present inventors have made better coatingsemploying a pH protective coating or layer 286 having an N-Parameterlower than 0.7, as described above. Alternatively, the N-parameter has avalue of at least 0.3, or from 0.4 to 0.6, or at least 0.53.

The rate of erosion, dissolution, or leaching (different names forrelated concepts) of the pH protective coating or layer 286, if directlycontacted by the fluid 218, is less than the rate of erosion of thebarrier coating or layer 288, if directly contacted by the fluid 218.

The thickness of the pH protective coating or layer is contemplated tobe from 50-500 nm, with a preferred range of 100-200 nm.

The pH protective coating or layer 286 is effective to isolate the fluid218 from the barrier coating or layer 288, at least for sufficient timeto allow the barrier coating to act as a barrier during the shelf lifeof the pharmaceutical package or other vessel 210.

The inventors have further found that certain pH protective coatings orlayers of SiO_(x)C_(y) or SiN_(x)C_(y) formed from cyclic polysiloxaneprecursors, which pH protective coatings or layers have a substantialorganic component, do not erode quickly when exposed to fluids, and infact erode or dissolve more slowly when the fluids have higher pHswithin the range of 5 to 9. For example, at pH 8, the dissolution rateof a pH protective coating or layer made from the precursoroctamethylcyclotetrasiloxane, or OMCTS, is quite slow. These pHprotective coatings or layers of SiO_(x)C_(y) or SiN_(x)C_(y) cantherefore be used to cover a barrier layer of SiOx, retaining thebenefits of the barrier layer by protecting it from the fluid in thepharmaceutical package. The protective layer is applied over at least aportion of the SiO_(x) layer to protect the SiO_(x) layer from contentsstored in a vessel, where the contents otherwise would be in contactwith the SiO_(x) layer.

Although the present invention does not depend upon the accuracy of thefollowing theory, it is further believed that effective pH protectivecoatings or layers for avoiding erosion can be made from cyclicsiloxanes and silazanes as described in this disclosure. SiO_(x)C_(y) orSiN_(x)C_(y) coatings deposited from cyclic siloxane or linear silazaneprecursors, for example octamethylcyclotetrasiloxane (OMCTS), arebelieved to include intact cyclic siloxane rings and longer series ofrepeating units of the precursor structure. These coatings are believedto be nanoporous but structured and hydrophobic, and these propertiesare believed to contribute to their success as pH protective coatings orlayers, and also protective coatings or layers. This is shown, forexample, in U.S. Pat. No. 7,901,783.

SiO_(x)C_(y) or SiN_(x)C_(y) coatings also can be deposited from linearsiloxane or linear silazane precursors, for example hexamethyldisiloxane(HMDSO) or tetramethyldisiloxane (TMDSO).

Optionally an FTIR absorbance spectrum of the pH protective coating orlayer 286 of any embodiment has a ratio greater than 0.75 between themaximum amplitude of the Si—O—Si symmetrical stretch peak normallylocated between about 1000 and 1040 cm-1, and the maximum amplitude ofthe Si—O—Si assymmetric stretch peak normally located between about 1060and about 1100 cm-1. Alternatively in any embodiment, this ratio can beat least 0.8, or at least 0.9, or at least 1.0, or at least 1.1, or atleast 1.2. Alternatively in any embodiment, this ratio can be at most1.7, or at most 1.6, or at most 1.5, or at most 1.4, or at most 1.3. Anyminimum ratio stated here can be combined with any maximum ratio statedhere, as an alternative embodiment.

Optionally, in any embodiment the pH protective coating or layer 286, inthe absence of the medicament, has a non-oily appearance. Thisappearance has been observed in some instances to distinguish aneffective pH protective coating or layer from a lubricity layer, whichin some instances has been observed to have an oily (i.e. shiny)appearance.

Optionally, for the pH protective coating or layer 286 in anyembodiment, the silicon dissolution rate by a 50 mM potassium phosphatebuffer diluted in water for injection, adjusted to pH 8 withconcentrated nitric acid, and containing 0.2 wt. % polysorbate-80surfactant, (measured in the absence of the medicament, to avoidchanging the dissolution reagent), at 40° C., is less than 170 ppb/day.(Polysorbate-80 is a common ingredient of pharmaceutical preparations,available for example as Tween®-80 from Uniqema Americas LLC, WilmingtonDel.)

Optionally, for the pH protective coating or layer 286 in anyembodiment, the silicon dissolution rate is less than 160 ppb/day, orless than 140 ppb/day, or less than 120 ppb/day, or less than 100ppb/day, or less than 90 ppb/day, or less than 80 ppb/day. Optionally,in any embodiment the silicon dissolution rate is more than 10 ppb/day,or more than 20 ppb/day, or more than 30 ppb/day, or more than 40ppb/day, or more than 50 ppb/day, or more than 60 ppb/day. Any minimumrate stated here can be combined with any maximum rate stated here forthe pH protective coating or layer 286 in any embodiment.

Optionally, for the pH protective coating or layer 286 in any embodimentthe total silicon content of the pH protective coating or layer andbarrier coating, upon dissolution into a test composition with a pH of 8from the vessel, is less than 66 ppm, or less than 60 ppm, or less than50 ppm, or less than 40 ppm, or less than 30 ppm, or less than 20 ppm.

pH Protective Coating or Layer Properties of any Embodiment Theory ofOperation

The inventors offer the following theory of operation of the pHprotective coating or layer described here. The invention is not limitedby the accuracy of this theory or to the embodiments predictable by useof this theory.

The dissolution rate of the SiO_(x) barrier layer is believed to bedependent on SiO bonding within the layer. Oxygen bonding sites(silanols) are believed to increase the dissolution rate.

It is believed that the OMCTS-based pH protective coating or layer bondswith the silanol sites on the SiO_(x) barrier layer to “heal” orpassivate the SiO_(x) surface and thus dramatically reduces thedissolution rate. In this hypothesis, the thickness of the OMCTS layeris not the primary means of protection—the primary means is passivationof the SiO_(x) surface. It is contemplated that a pH protective coatingor layer as described in this specification can be improved byincreasing the crosslink density of the pH protective coating or layer.

Use of a coating or layer according to any described embodiment iscontemplated as a pH protective coating or layer preventing dissolutionof the barrier coating in contact with a fluid.

EXAMPLES Example 1: Conditions for Production of pH Protective Layer

Some conditions optionally used for production of pH Protective Layersare shown in Table 1.

TABLE 1 OMCTS-BASED PLASMA PH PROTECTIVE COATING OR LAYER MADE WITHCARRIER GAS pH protective protective protective Carrier pH protective pHprotective coating or OMCTS O2 Gas (Ar) coating or Example coating or PHprotective layer Time Flow Rate Flow Rate Flow Rate layer Power 1 runlayer Type Monomer (sec) (sccm) (sccm) (sccm) (Watts) A Uncoated n/a n/an/a n/a n/a n/a (Control) COC B Silicon oil n/a n/a n/a n/a n/a n/a(Industry on COC Standard) C L3 lubricity OMCTS 10 sec 3 0 65 6 (withoutcoating or Oxygen) layer over SiO_(x) on COC D L2 pH OMCTS 10 sec 3 1 656 (with protective Oxygen) coating or layer over SiO_(x) on COC

Examples 2-5

Vessel samples were produced as follows. A COC 8007 vessel was producedaccording to the Protocol for Forming COC Vessel. An SiO_(x) barriercoating or layer was applied to the vessels according to the Protocolfor Coating COC Vessel Interior with SiO_(x). A pH protective coating orlayer was applied to the SiO_(x) coated vessels according to theProtocol for Coating COC Vessel Interior with OMCTS, modified asfollows. Argon carrier gas and oxygen were used where noted in Table 2.

The process conditions were set to the following, or as indicated inTable 2:

-   -   OMCTS—3 sccm (when used)    -   Argon gas—7.8 sccm (when used)    -   Oxygen 0.38 sccm (when used)    -   Power—3 watts    -   Power on time—10 seconds        Vessels 2, 3, and 4 of the corresponding example numbers were        tested to determine total extractable silicon levels        (representing extraction of the organosilicon-based PECVD pH        protective coating or layer) using the Protocol for Measuring        Dissolved Silicon in a Vessel, modified and supplemented as        shown in this example.

The silicon was extracted using saline water digestion. The vessel wasfilled with two milliliters of 0.9% aqueous saline solution and sealed.The vessel was set into a PTFE test stand and placed in an oven at 50°C. for 72 hours.

Then, the saline solution was removed from the vesseland the fluidobtained from each vessel was brought to a volume of 50 ml using18.2M0-cm deionized water and further diluted 2× to minimize sodiumbackground during analysis.

Next, the fluid recovered from each vessel was tested for extractablesilicon using the Protocol for Measuring Dissolved Silicon in a Vessel.The instrument used was a Perkin Elmer Elan DRC II equipped with a CetacASX-520 autosampler. The following ICP-MS conditions were employed:

-   -   Nebulizer: Quartz Meinhardt    -   Spray Chamber: Cyclonic    -   RF (radio frequency) power: 1550 Watts    -   Argon (Ar) Flow: 15.0 L/min    -   Auxiliary Ar Flow: 1.2 L/min    -   Nebulizer Gas Flow: 0.88 L/min    -   Integration time: 80 sec    -   Scanning mode: Peak hopping    -   RPq (The RPq is a rejection parameter) for Cerium as CeO (m/z        156: <2%

Aliquots from aqueous dilutions obtained from vessels 2, 3, and 4 wereinjected and analyzed for Si in concentration units of micrograms perliter. The results of this test are shown in Table 2. While the resultsare not quantitative, they do indicate that extractables from the pHprotective coating or layer are not clearly higher than the extractablesfor the SiO_(x) barrier layer only.

TABLE 2 OMCTS PH PROTECTIVE COATING OR LAYER ((Ex. 2 and 3)) ExampleOMCTS O₂ Ar (Vessel) (sccm) (sccm) (sccm) 2 3.0 0.38 7.8 3 3.0 0.38 7.84 n/a n/a n/a (SiO_(x)only) 5 n/a n/a n/a (silicon oil)

Examples 6-8

Vessel samples 6, 7, and 8, employing three different pH protectivecoatings or layers, were produced in the same manner as for Examples 2-5except as otherwise indicated in Table 3:

Vessel 6 had a three-component pH protective coating or layer employingOMCTS, oxygen, and carrier gas. Vessel 7 had a two component pHprotective coating or layer employing OMCTS and oxygen, but no carriergas. Vessel 8 had a one-component pH protective coating or layer (OMCTSonly). Vessels 6-8 were then tested for lubricity as described forExamples 2-5.

The pH protective coatings or layers produced according to these workingexamples are also contemplated to function as protective coatings orlayers to increase the shelf life of the vessels, compared to similarvessels provided with a barrier coating or layer but no pH protectivecoating or layer.

TABLE 3 OMCTS pH PROTECTIVE COATING OR LAYER OMCTS - 2.5 sccm Argongas - 7.6 sccm (when used) Oxygen 0.38 sccm (when used) Power - 3 wattsPower on time - 10 seconds

Examples 9-11

Examples 6-8 using an OMCTS precursor gas were repeated in Examples9-11, except that HMDSO was used as the precursor in Examples 9-11. Theresults are shown in Table 4. The coatings produced according to theseworking examples are contemplated to function as pH protective coatingsor layers, and also as protective coatings or layers to increase theshelf life of the vessels, compared to similar vessels provided with abarrier coating or layer but no pH protective coating or layer.

TABLE 4 HMDSO pH PROTECTIVE COATING OR LAYER HMDSO O₂ Ar Example (sccm)(sccm) (sccm) 9 2.5 0.38 7.6 10 2.5 0.38 — 11 2.5 — —

Example 12: PH Protective Coating or Layer Extractables

Silicon extractables from vessels were measured using ICP-MS analysis asdescribed in the Protocol for Measuring Dissolved Silicon in a Vessel.The vessels were evaluated in both static and dynamic situations. TheProtocol for Measuring Dissolved Silicon in a Vessel, modified asfollows, describes the test procedure:

-   -   Vessel filled with 2 ml of 0.9% saline solution    -   Vessel placed in a stand—stored at 50° C. for 72 hours.    -   After 72 hours saline solution test for dissolved silicon    -   Dissolved silicon measured before and after saline solution        expelled from vessel.

The extractable Silicon Levels from a silicon oil coated glass vesseland a protective coated and SiO_(x) coated COC vessel are shown in Table5. Precision of the ICP-MS total silicon measurement is +/−3%.

TABLE 5 Silicon Extractables Comparison of SiO_(x)C_(y)H_(z) CoatingsDynamic Vessel Type Static (ug/L) (ug/L) Cyclic olefin vessel withSiO_(x)C_(y)H_(z) coating 70 81 Borosilicate glass vessel with siliconeoil 825 835Summary of Lubricity and/or Protective Measurements

Table 6 shows a summary of the above OMCTS coatings or layers

TABLE 6 Summary Table of OMCTS PH PROTECTIVE COATING OR LAYER FromSelected Previous Examples OMCTS Power Dep Time Example (sccm) O₂ (sccm)Ar (sccm) (Watt) (sec) 1C 3.0 0.00 65 6 10 1D 3.0 1.00 65 6 10 2 3.00.38 7.8 6 10 3 3.0 0.38 7.8 6 10 6 2.5 0.38 7.6 6 10 7 2.5 0.38 0.0 610 8 2.5 0.00 0.0 6 10

Comparative Example 13: Dissolution of SiO_(x) Coating Versus pH

The Protocol for Measuring Dissolved Silicon in a Vessel is followed,except as modified here. Test solutions—50 mM buffer solutions at pH 3,6, 7, 8, 9, and 12 are prepared. Buffers are selected having appropriatepKa values to provide the pH values being studied. A potassium phosphatebuffer is selected for pH 3, 7, 8 and 12, a sodium citrate buffer isutilized for pH 6 and tris buffer is selected for pH 9. 3 ml of eachtest solution is placed in borosilicate glass 5 ml pharmaceuticalvessels and SiOx coated 5 ml thermoplastic pharmaceutical vessels. Thevessels are all closed with standard coated stoppers and crimped. Thevessels are placed in storage at 20-25° C. and pulled at various timepoints for inductively coupled plasma spectrometer (ICP) analysis of Sicontent in the solutions contained in the vessels, in parts per billion(ppb) by weight, for different storage times.

The Protocol for Determining Average Dissolution Rate Si content is usedto monitor the rate of glass dissolution, except as modified here. Thedata is plotted to determine an average rate of dissolution ofborosilicate glass or SiOx coating at each pH condition. Representativeplots at pH 6 through 8 are FIGS. 4-6.

The rate of Si dissolution in ppb is converted to a predicted thickness(nm) rate of Si dissolution by determining the total weight of Siremoved, then using a surface area calculation of the amount of vesselsurface (11.65 cm²) exposed to the solution and a density of SiOx of 2.2g/cm³. FIG. 7 shows the predicted initial thickness of the SiOx coatingrequired, based on the conditions and assumptions of this example(assuming a residual SiOx coating of at least 30 nm at the end of thedesired shelf life of two years, and assuming storage at 20 to 25° C.).As FIG. 7 shows, the predicted initial thickness of the coating is about36 nm at pH 5, about 80 nm at pH 6, about 230 nm at pH 7, about 400 nmat pH 7.5, about 750 nm at pH 8, and about 2600 nm at pH 9.

The coating thicknesses in FIG. 7 represent atypically harsh casescenarios for pharma and biotech products. As a general rule of thumb,storage at a lower temperature reduces the thickness required, all otherconditions being equivalent.

The following conclusions are reached, based on this test. First, theamount of dissolved Si in the SiOx coating or glass increasesexponentially with increasing pH. Second, the SiOx coating dissolvesmore slowly than borosilicate glass at a pH lower than 8. The SiOxcoating shows a linear, monophasic dissolution over time, whereasborosilicate glass tends to show a more rapid dissolution in the earlyhours of exposure to solutions, followed by a slower linear dissolution.This may be due to surface accumulation of some salts and elements onborosilicate during the forming process relative to the uniformcomposition of the SiOx coating. This result incidentally suggests theutility of an SiOx coating on the wall of a borosilicate glass vessel toreduce dissolution of the glass at a pH lower than 8. Third, PECVDapplied barrier coatings for vessels in which pharmaceuticalpreparations are stored will need to be adapted to the specificpharmaceutical preparation and proposed storage conditions (or viceversa), at least in some instances in which the pharmaceuticalpreparation interacts with the barrier coating significantly.

Example 14

An experiment is conducted with vessels coated with SiOx coating+OMCTSpH protective coating or layer, to test the pH protective coating orlayer for its functionality as a protective coating or layer. Thevessels are 5 mL vessels (the vessels are normally filled with productto 5 mL; their capacity without headspace, when capped, is about 7.5 mL)composed of cyclic olefin co-polymer (COC, Topas® 6013M-07).

Sixty vessels are coated on their interior surfaces with an SiO_(x)coating produced in a plasma enhanced chemical vapor deposition (PECVD)process using a HMDSO precursor gas according to the Protocol forCoating Tube Interior with SiOx set forth above, except that equipmentsuitable for coating a vessel is used. The following conditions areused.

-   -   HMDSO flow rate: 0.47 sccm    -   Oxygen flow rate: 7.5 sccm    -   RF power: 70 Watts    -   Coating time: 12 seconds (includes a 2-sec RF power ramp-up        time)

Next the SiOx coated vessels are coated over the SiO_(x) with anSiO_(x)C_(y) coating produced in a PECVD process using an OMCTSprecursor gas according to the Protocol for Coating COC Vessel Interiorwith OMCTS Lubricity Coating set forth above, except that the samecoating equipment is used as for the SiO_(x) coating. The followingconditions are used.

-   -   OMCTS flow rate: 2.5 sccm    -   Argon flow rate: 10 sccm    -   Oxygen flow rate: 0.7 sccm    -   RF power: 3.4 Watts    -   Coating time: 5 seconds

Eight vessels are selected and the total deposited quantity of PECVDcoating (SiO_(x)+SiO_(x)C_(y)) is determined with a Perkin Elmer OptimaModel 7300DV ICP-OES instrument, using the Protocol for Total SiliconMeasurement set forth above. This measurement determines the totalamount of silicon in both coatings, and does not distinguish between therespective SiO_(x) and SiO_(x)C_(y) coatings. The results are shownbelow.

Example, Vessel Total Silicon ug/L 14-1 13844 14-2 14878 14-3 14387 14-413731 14-5 15260 14-6 15017 14-7 15118 14-8 12736 Mean 14371 StdDev 877Quantity of SiO_(x) + Lubricity layer on Vessels

In the following work, except as indicated otherwise in this example,the Protocol for Determining Average Dissolution Rate is followed. Twobuffered pH test solutions are used in the remainder of the experiment,respectively at pH 4 and pH 8 to test the effect of pH on dissolutionrate. Both test solutions are 50 mM buffers using potassium phosphate asthe buffer, diluted in water for injection (WFI) (0.1 um sterilized,filtered). The pH is adjusted to pH 4 or 8, respectively, withconcentrated nitric acid.

25 vessels are filled with 7.5 ml per vessel of pH 4 buffered testsolution and 25 other vessels are filled with 7.5 ml per vessel of pH 4buffered test solution (note the fill level is to the top of thevessel—no head space). The vessels are closed using prewashed butylstoppers and aluminum crimps. The vessels at each pH are split into twogroups. One group at each pH containing 12 vessels is stored at 4° C.and the second group of 13 vessels is stored at 23° C.

The vessels are sampled at Days 1, 3, 6, and 8. The Protocol forMeasuring Dissolved Silicon in a Vessel is used, except as otherwiseindicated in this example. The analytical result is reported on thebasis of parts per billion of silicon in the buffered test solutions ofeach vessel. A dissolution rate is calculated in terms of parts perbillion per day as described above in the Protocol for DeterminingAverage Dissolution Rate. The results at the respective storagetemperatures follow:

Shelf Life Conditions 23° C. Vessel SiO_(x) + Vessel SiO_(x) + LubricityCoating at Lubricity Coating at pH 4 pH 8 Si Dissolution Rate 31 7(PPB/day) Shelf Life Conditions 4° C. Vessel SiO_(x) + Lubricity Coatingat Vessel SiO_(x) + Lubricity pH 4 Coating at pH 8 Si Dissolution Rate 711 (PPB/day)

The observations of Si dissolution versus time for the OMCTS-basedcoating at pH8 and pH 4 indicate the pH 4 rates are higher at ambientconditions. Thus, the pH 4 rates are used to determine how much materialwould need to be initially applied to leave a coating of adequatethickness at the end of the shelf life, taking account of the amount ofthe initial coating that would be dissolved. The results of thiscalculation are:

Vessel SiO_(x) + Lubricity Coating at pH 4 Si Dissolution Rate (PPB/day)31 Mass of Coating Tested (Total Si) 14,371 Shelf Life (days) at 23° C.464 Shelf Life (years) at 23° C. 1.3 Required Mass of Coating (TotalSi) - 2 years 22,630 Required Mass of Coating (Total Si) - 3 years33,945 Shelf Life Calculation

Based on this calculation, the OMCTS protective layer needs to be about2.5 times thicker—resulting in dissolution of 33945 ppb versus the14,371 ppb representing the entire mass of coating tested—to achieve a3-year calculated shelf life.

Example 15

The results of Comparative Example 13 and Example 14 above can becompared as follows, where the “pH protective coating or layer” is thecoating of SiO_(x)C_(y) referred to in Example BB.

Shelf Life Conditions - pH 8 and 23° C. Vessel SiO_(x) + LubricityVessel SiO_(x) Coating Si Dissolution Rate (PPB/day) 1,250 7

This data shows that the silicon dissolution rate of SiO_(x) alone isreduced by more than 2 orders of magnitude at pH 8 in vessels alsocoated with SiO_(x)C_(y) coatings.

Another comparison is shown by the following data from several differentexperiments carried out under similar accelerated dissolutionconditions.

Silicon Dissolution with pH 8 at 40° C. (ug/L) Vessel Coating 1 2 3 4 710 15 Description day days days days days days days A. SiO_(x) made withHMDSO 165 211 226 252 435 850 1,364 Plasma + Si_(w)O_(x)C_(y) or itsequivalent SiO_(x)C_(y) made with OMCTS Plasma B. Si_(w)O_(x)C_(y) orits 109 107 76 69 74 158 198 equivalent SiO_(x)C_(y) made with OMCTSPlasma C. SiO_(x) made with HMDSO 2,504 4,228 5,226 5,650 9,292 10,1779,551 Plasma D. SiO_(x) made with HMDSO 1,607 1,341 3,927 10,182 18,14820,446 21,889 Plasma + Si_(w)O_(x)C_(y) or its equivalent SiO_(x)C_(y)made with HMDSO Plasma E. Si_(w)O_(x)C_(y) or its 1,515 1,731 1,8131,743 2,890 3,241 3,812 equivalent SiO_(x)C_(y) made with HMDSO Plasma

Row A (SiO_(x) with OMCTS coating) versus C (SiO_(x) without OMCTScoating) show that the OMCTS pH protective coating or layer is also aneffective protective coating or layer to the SiO_(x) coating at pH 8.The OMCTS coating reduced the one-day dissolution rate from 2504 ug/L(“u” or μ or the Greek letter “mu” as used herein are identical, and areabbreviations for “micro”) to 165 ug/L.

Example 16

Samples 1-6 as listed in Table 7 were prepared as described in Example13, with further details as follows.

A cyclic olefin copolymer (COC) resin was injection molded to form abatch of 5 ml vessels. Silicon chips were adhered with double-sidedadhesive tape to the internal walls of the vessels. The vessels andchips were coated with a two layer coating by plasma enhanced chemicalvapor deposition (PECVD). The first layer was composed of SiOx withbarrier properties as defined in the present disclosure, and the secondlayer was an SiOxCy pH protective coating or layer.

A precursor gas mixture comprising OMCTS, argon, and oxygen wasintroduced inside each vessel. The gas inside the vessel was excitedbetween capacitively coupled electrodes by a radio-frequency (13.56 MHz)power source. The monomer flow rate (Fm) in units of sccm, oxygen flowrate (Fo) in units of sccm, argon flowrate in sccm, and power (W) inunits of watts are shown in Table 7.

A composite parameter, W/FM in units of kJ/kg, was calculated fromprocess parameters W, Fm, Fo and the molecular weight, M in g/mol, ofthe individual gas species. W/FM is defined as the energy input per unitmass of polymerizing gases. Polymerizing gases are defined as thosespecies that are incorporated into the growing coating such as, but notlimited to, the monomer and oxygen. Non-polymerizing gases, by contrast,are those species that are not incorporated into the growing coating,such as but not limited to argon, helium and neon.

In this test, PECVD processing at high W/FM is believed to have resultedin higher monomer fragmentation, producing organosiloxane coatings withhigher cross-link density. PECVD processing at low W/FM, by comparison,is believed to have resulted in lower monomer fragmentation producingorganosiloxane coatings with a relatively lower cross-link density.

The relative cross-link density of samples 5, 6, 2, and 3 was comparedbetween different coatings by measuring FTIR absorbance spectra. Thespectra of samples 5, 6, 2, and 3 are provided in FIGS. 11-14. In eachspectrum, the ratio of the peak absorbance at the symmetric stretchingmode (1000-1040 cm-1) versus the peak absorbance at the asymmetricstretching mode (1060-1100 cm-1) of the Si—O—Si bond was measured, andthe ratio of these two measurements was calculated, all as shown inTable 7. The respective ratios were found to have a linear correlationto the composite parameter W/FM as shown in FIGS. 9-10.

A qualitative relation—whether the coating appeared oily (shiny, oftenwith irridescence) or non-oily (non-shiny) when applied on the siliconchips—was also found to correlate with the W/FM values in Table 7. Oilyappearing coatings deposited at lower W/FM values, as confirmed by Table7, are believed to have a lower crosslink density, as determined bytheir lower sym/asym ratio, relative to the non-oily coatings that weredeposited at higher W/FM and a higher cross-link density. The onlyexception to this general rule of thumb was sample 2 in Table 7. It isbelieved that the coating of sample 2 exhibited a non-oily appearancebecause it was was too thin to see. Thus, an oilyness observation wasnot reported in Table 7 for sample 2. The chips were analyzed by FTIR intransmission mode, with the infrared spectrum transmitted through thechip and sample coating, and the transmission through an uncoated nullchip subtracted.

Non-oily organosiloxane layers produced at higher W/FM values, whichprotect the underlying SiOx coating from aqueous solutions at elevatedpH and temperature, were preferred because they provided lower Sidissolution and a longer shelf life, as confirmed by Table 7. Forexample, the calculated silicon dissolution by contents of the vessel ata pH of 8 and 40° C. was reduced for the non-oily coatings, and theresulting shelf life was 1381 days in one case and 1147 days in another,as opposed to the much shorter shelf lives and higher rates ofdissolution for oily coatings. Calculated shelf life was determined asshown for Example 13. The calculated shelf life also correlated linearlyto the ratio of symmetric to asymmetric stretching modes of the Si—O—Sibond in organosiloxane pH protective coatings or layers.

Sample 6 can be particularly compared to Sample 5. An organosiloxane, pHprotective coating or layer was deposited according to the processconditions of sample 6 in Table 7. The coating was deposited at a highW/FM. This resulted in a non-oily coating with a high Si—O—Si sym/asymratio of 0.958, which resulted in a low rate of dissolution of 84.1ppb/day (measured by the Protocol for Determining Average DissolutionRate) and long shelf life of 1147 days (measured by the Protocol forDetermining Calculated Shelf Life). The FTIR spectra of this coatingexhibits a relatively similar asymmetric Si—O—Si peak absorbancecompared to the symmetric Si—O—Si peak absorbance. This is an indicationof a higher cross-link density coating, which is a preferredcharacteristic for pH protection and long shelf life.

An organosiloxane pH protective coating or layer was deposited accordingto the process conditions of sample 5 in Table 7. The coating wasdeposited at a moderate W/FM. This resulted in an oily coating with alow Si—O—Si sym/asym ratio of 0.673, which resulted in a high rate ofdissolution of 236.7 ppb/day (following the Protocol for DeterminingAverage Dissolution Rate) and shorter shelf life of 271 days (followingthe Protocol for Determining Calculated Shelf Life). The FTIR spectrumof this coating exhibits a relatively high asymmetric Si—O—Si peakabsorbance compared to the symmetric Si—O—Si peak absorbance. This is anindication of a lower cross-link density coating, which is contemplatedto be an unfavorable characteristic for pH protection and long shelflife.

Sample 2 can be particularly compared to Sample 3. A pH protectivecoating or layer was deposited according to the process conditions ofsample 2 in Table 7. The coating was deposited at a low W/FM. Thisresulted in a coating that exhibited a low Si—O—Si sym/asym ratio of0.582, which resulted in a high rate of dissolution of 174 ppb/day andshort shelf life of 107 days. The FTIR spectrum of this coating exhibitsa relatively high asymmetric Si—O—Si peak absorbance compared to thesymmetric Si—O—Si peak absorbance. This is an indication of a lowercross-link density coating, which is an unfavorable characteristic forpH protection and long shelf life.

An organosiloxane, pH protective coating or layer was depositedaccording to the process conditions of sample 3 in Table 7. The coatingwas deposited at a high W/FM. This resulted in a non-oily coating with ahigh Si—O—Si sym/asym ratio of 0.947, which resulted in a low rate of Sidissolution of 79.5 ppb/day (following the Protocol for DeterminingAverage Dissolution Rate) and long shelf life of 1381 days (followingthe Protocol for Determining Calculated Shelf Life). The FTIR spectrumof this coating exhibits a relatively similar asymmetric Si—O—Si peakabsorbance compared to the symmetric Si—O—Si peak absorbance. This is anindication of a higher cross-link density coating, which is a preferredcharacteristic for pH protection and long shelf life.

TABLE 7 FTIR Absorbance Process Parameters Si Dissoution @ pH 8/40° C.Si—O—Si Si—O—Si Flow O₂ Total Shelf Rate of sym stretch asym stretchRatio Rate Flow Power W/FM Si life Dissolution (1000- (1160- Si—O—SiSamples OMCTS Ar Rate (W) (kJ/kg) (ppb) (days) (ppb/day) 1040 cm⁻¹) 1100cm⁻¹) (sym/asym) Oilyness 1 3 10 0.5 14 21613 43464 385 293.18 0.1530.219 0.700 YES 2 3 20 0.5 2 3088 7180 107 174.08 0.011 0.020 0.582 NA 31 20 0.5 14 62533 42252.17 1381 79.53 0.093 0.098 0.947 NO 4 2 15 0.5 818356 27398 380 187.63 0.106 0.141 0.748 YES 5 3 20 0.5 14 21613 24699271 236.73 0.135 0.201 0.673 YES 6 1 10 0.5 14 62533 37094 1147 84.10.134 0.140 0.958 NO

Example 17

An experiment similar to Example 14 was carried out, modified asindicated in this example and in Table 8 (where the results aretabulated). 100 5 mL COP vessels were made and coated with an SiOxbarrier layer and an OMCTS-based pH protective coating or layer asdescribed previously, except that for Sample PC194 only the pHprotective coating or layer was applied. The coating quantity was againmeasured in parts per billion extracted from the surfaces of the vesselsto remove the entire pH protective coating or layer, as reported inTable 8.

In this example, several different coating dissolution conditions wereemployed. The test solutions used for dissolution contained either 0.02or 0.2 wt. % polysorbate-80 surfactant, as well as a buffer to maintaina pH of 8. Dissolution tests were carried out at either 23° C. or 40° C.

Multiple vessels were filled with each test solution, stored at theindicated temperature, and analyzed at several intervals to determinethe extraction profile and the amount of silicon extracted. An averagedissolution rate for protracted storage times was then calculated byextrapolating the data obtained according to the Protocol forDetermining Average Dissolution Rate. The results were calculated asdescribed previously and are shown in Table 8. Of particular note, asshown on Table 8, were the very long calculated shelf lives of thefilled packages provided with a PC 194 pH protective coating or layer:

21045 days (over 57 years) based on storage at a pH of 8, 0.02 wt. %polysorbate-80 surfactant, at 23° C.;

38768 days (over 100 years) based on storage at a pH of 8, 0.2 wt. %polysorbate-80 surfactant, at 23° C.;

8184 days (over 22 years) based on storage at a pH of 8, 0.02 wt. %polysorbate-80 surfactant, at 40° C.; and

14732 days (over 40 years) based on storage at a pH of 8, 0.2 wt. %polysorbate-80 surfactant, at 40° C.

Referring to Table 8, the longest calculated shelf lives correspondedwith the use of an RF power level of 150 Watts and a corresponding highW/FM value. It is believed that the use of a higher power level causeshigher cross-link density of the pH protective coating or layer.

TABLE 8 OMCTS Argon O₂ Plasma Total Si Calculated Average Rate Flow RateFlow Rate Flow Rate Power Duration W/FM (ppb) (OMCTS) Shelf-life ofDissolution Sample (sccm) (sccm) (sccm) (W) (sec) (kJ/kg) layer) (days)(ppb/day) Process Parameters Si Dissolution @ pH 8/23° C./0.02%Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 21045 3.5 018 1.0 200.5 18 15 77157 42982 1330 32.3 Process Parameters Si Dissolution @ pH8/23° C./0.2% Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 38768 1.9018 1.0 20 0.5 18 15 77157 42982 665 64.6 048 4 80 2 35 20 37507 565201074 52.62 Process Parameters Si Dissolution @ pH 8/40° C./0.02%Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 8184 9 018 1.0 20 0.518 15 77157 42982 511 84 Process Parameters Si Dissolution @ pH 8/40°C./0.2% Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 14732 5 018 1.020 0.5 18 15 77157 42982 255 168

Example 18

Another series of experiments similar to those of Example 17 are run,showing the effect of progressively increasing the RF power level on theFTIR absorbance spectrum of the pH protective coating or layer. Theresults are tabulated in Table 9, which in each instance shows asymmetric/assymmetric ratio greater than 0.75 between the maximumamplitude of the Si—O—Si symmetrical stretch peak normally locatedbetween about 1000 and 1040 cm-1, and the maximum amplitude of theSi—O—Si assymmetric stretch peak normally located between about 1060 andabout 1100 cm-1. Thus, the symmetric/assymmetric ratio is 0.79 at apower level of 20 W, 1.21 or 1.22 at power levels of 40, 60, or 80 W,and 1.26 at 100 Watts under otherwise comparable conditions.

The 150 Watt data in Table 9 is taken under somewhat differentconditions than the other data, so it is not directly comparable withthe 20-100 Watt data discussed above. The FTIR data of samples 6 and 8of Table 9 was taken from the upper portion of the vessel and the FTIRdata of samples 7 and 9 of Table 9 was taken from the lower portion ofthe vessel. Also, the amount of OMCTS was cut in half for samples 8 and9 of Table 9, compared to samples 6 and 7. Reducing the oxygen levelwhile maintaining a power level of 150 W raised the symmetric/asymmetricratio still further, as shown by comparing samples 6 and 7 to samples 8and 9 in Table 9.

It is believed that, other conditions being equal, increasing thesymmetric/asymmetric ratio increases the shelf life of a vessel filledwith a material having a pH exceeding 5.

Table 10 shows the calculated O-Parameters and N-Parameters (as definedin U.S. Pat. No. 8,067,070) for the experiments summarized in Table 9.As Table 10 shows, the O-Parameters ranged from 0.134 to 0.343, and theN-Parameters ranged from 0.408 to 0.623—all outside the ranges claimedin U.S. Pat. No. 8,067,070.

TABLE 9 OMCTS Argon O₂ Plasma Symmetric Assymetric Symmetric/ Flow RateFlow Rate Flow Rate Power Duration W/FM Stretch Peak Stretch PeakAssymetric Samples (sccm) (sccm) (sccm) (W) (sec) (kJ/kg) at 1000-1040cm−¹ at 1060-1100 cm−¹ Ratio ID Process Parameters FTIR Results 1 1 200.5 20 20 85,730 0.0793 0.1007 0.79 2 1 20 0.5 40 20 171,460 0.06190.0507 1.22 3 1 20 0.5 60 20 257,190 0.1092 0.0904 1.21 4 1 20 0.5 80 20342,919 0.1358 0.1116 1.22 5 1 20 0.5 100 20 428,649 0.209 0.1658 1.26 61 20 0.5 150 20 642,973 0.2312 0.1905 1.21 7 1 20 0.5 150 20 642,9730.2324 0.1897 1.23 8 0.5 20 0.5 150 20 1,223,335 0.1713 0.1353 1.27 90.5 20 0.5 150 20 1,223,335 0.1475 0.1151 1.28

TABLE 10 OMCTS Argon O₂ Plasma Samples Flow Rate Flow Rate Flow RatePower Duration W/FM O- N- ID (sccm) (sccm) (sccm) (W) (sec) (kJ/kg)Parameter Parameter Process Parameters 1 1 20 0.5 20 20 85,730 0.3430.436 2 1 20 0.5 40 20 171,460 0.267 0.408 3 1 20 0.5 60 20 257,1900.311 0.457 4 1 20 0.5 80 20 342,919 0.270 0.421 5 1 20 0.5 100 20428,649 0.177 0.406 6 1 20 0.5 150 20 642,973 0.151 0.453 7 1 20 0.5 15020 642,973 0.151 0.448 8 0.5 20 0.5 150 20 1,223,335 0.134 0.623 9 0.520 0.5 150 20 1,223,335 0.167 0.609

Optionally in any embodiment of the vessel, the barrier coating or layercomprises SiOx, where x is from 1.5 to 2.9.

Optionally in any embodiment of the vessel, the barrier coating or layerconsists essentially of SiOx, where x is from 1.5 to 2.9.

Optionally in any embodiment of the vessel, the barrier coating or layeris deposited by vapor deposition.

Optionally in any embodiment of the vessel, the barrier coating or layeris deposited by chemical vapor deposition.

Optionally in any embodiment of the vessel, the barrier coating or layeris deposited by plasma enhanced chemical vapor deposition.

Optionally in any embodiment of the vessel, the pH protective coating orlayer is deposited by vapor deposition.

Optionally in any embodiment of the vessel, the pH protective coating orlayer is deposited by chemical vapor deposition.

Optionally in any embodiment of the vessel, the pH protective coating orlayer is deposited by plasma enhanced chemical vapor deposition. GradedComposite Layer

Another expedient contemplated here, for adjacent layers of SiO_(x) anda pH protective coating or layer, is a graded composite of any two ormore adjacent PECVD layers, for example the barrier coating or layer 288and a pH protective coating or layer 286. A graded composite can beseparate layers of a pH protective and/or barrier layer or coating witha transition or interface of intermediate composition between them, orseparate layers of a protective and/or hydrophobic layer and SiO_(x)with an intermediate distinct pH protective coating or layer ofintermediate composition between them, or a single coating or layer thatchanges continuously or in steps from a composition of a protectiveand/or hydrophobic layer to a composition more like SiO_(x), goingthrough the pH protective coating or layer in a normal direction.

The grade in the graded composite can go in either direction. Forexample, the composition of SiO_(x) can be applied directly to thesubstrate and graduate to a composition further from the surface of a pHprotective coating or layer, and optionally can further graduate toanother type of coating or layer, such as a hydrophobic coating or layeror a lubricity coating or layer. Additionally, in any embodiment anadhesion coating or layer, for example Si_(w)O_(x)C_(y), or itsequivalent SiO_(x)C_(y), optionally can be applied directly to thesubstrate before applying the barrier layer. A graduated pH protectivecoating or layer is particularly contemplated if a layer of onecomposition is better for adhering to the substrate than another, inwhich case the better-adhering composition can, for example, be applieddirectly to the substrate. It is contemplated that the more distantportions of the graded pH protective coating or layer can be lesscompatible with the substrate than the adjacent portions of the gradedpH protective coating or layer, since at any point the pH protectivecoating or layer is changing gradually in properties, so adjacentportions at nearly the same depth of the pH protective coating or layerhave nearly identical composition, and more widely physically separatedportions at substantially different depths can have more diverseproperties. It is also contemplated that a pH protective coating orlayer portion that forms a better barrier against transfer of materialto or from the substrate can be directly against the substrate, toprevent the more remote pH protective coating or layer portion thatforms a poorer barrier from being contaminated with the materialintended to be barred or impeded by the barrier.

The applied coatings or layers, instead of being graded, optionally canhave sharp transitions between one layer and the next, without asubstantial gradient of composition. Such pH protective coating or layercan be made, for example, by providing the gases to produce a layer as asteady state flow in a non-plasma state, then energizing the system witha brief plasma discharge to form a coating or layer on the substrate. Ifa subsequent coating or layer is to be applied, the gases for theprevious coating or layer are cleared out and the gases for the nextcoating or layer are applied in a steady-state fashion before energizingthe plasma and again forming a distinct layer on the surface of thesubstrate or its outermost previous coating or layer, with little if anygradual transition at the interface.

Common Conditions for All Embodiments

In any embodiment contemplated here, many common conditions can be used,for example any of the following, in any combination. For example, thelow-pressure PECVD process described in U.S. Pat. No. 7,985,188 can beused. A brief synopsis of that process follows.

The organosilicon precursor for the protective layer can include any ofthe following precursors useful for PECVD. The precursor for the PECVDcoating or layer of the present invention is broadly defined as anorganometallic precursor. An organometallic precursor is defined in thisspecification as comprehending compounds of metal elements from GroupIII and/or Group IV of the Periodic Table having organic residues, forexample hydrocarbon, aminocarbon or oxycarbon residues. Organometalliccompounds as presently defined include any precursor having organicmoieties bonded to silicon or other Group III/IV metal atoms directly,or optionally bonded through oxygen or nitrogen atoms. The relevantelements of Group III of the Periodic Table are Boron, Aluminum,Gallium, Indium, Thallium, Scandium, Yttrium, and Lanthanum, Aluminumand Boron being preferred. The relevant elements of Group IV of thePeriodic Table are Silicon, Germanium, Tin, Lead, Titanium, Zirconium,Hafnium, and Thorium, with Silicon and Tin being preferred. Othervolatile organic compounds can also be contemplated. However,organosilicon compounds are preferred for performing present invention.

An organosilicon precursor is contemplated, where an “organosiliconprecursor” is defined throughout this specification most broadly as acompound having the linkage:

The structure immediately above is a tetravalent silicon atom connectedto an oxygen atom and an organic carbon atom (an organic carbon atombeing a carbon atom bonded to at least one hydrogen atom). Optionally,the organosilicon precursor is selected from the group consisting of alinear siloxane, a monocyclic siloxane, a polycyclic siloxane, apolysilsesquioxane, a linear silazane, a monocyclic silazane, apolycyclic silazane, a polysilsesquiazane, and a combination of any twoor more of these precursors. Also contemplated as a precursor, thoughnot within the two formulas immediately above, is an alkyltrimethoxysilane.

If an oxygen-containing precursor (for example a siloxane) is used, arepresentative predicted empirical composition resulting from PECVDunder conditions forming a coating or layer would beSi_(w)O_(x)C_(y)H_(z) or its equivalent SiO_(x)C_(y) as defined in theDefinition Section, while a representative predicted empiricalcomposition resulting from PECVD under conditions forming a barriercoating or layer would be SiO_(x), where x in this formula is from about1.5 to about 2.9.

One type of precursor starting material having the above empiricalformula is a linear siloxane, for example a material having thefollowing formula:

in which each R is independently selected from alkyl, for examplemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl,alkyne, or others, and n is 1, 2, 3, 4, or greater, optionally two orgreater. Several examples of contemplated linear siloxanes arehexamethyldisiloxane (HMDSO),octamethyltrisiloxane,decamethyltetrasiloxane,dodecamethylpentasiloxane,or combinations of two or more of these.

Another type of precursor starting material, among the preferredstarting materials in the present context, is a monocyclic siloxane, forexample a material having the following structural formula:

in which R is defined as for the linear structure and “a” is from 3 toabout 10, or the analogous monocyclic silazanes. Several examples ofcontemplated hetero-substituted and unsubstituted monocyclic siloxanesand silazanes include

-   1,3,5-trimethyl-1,3,5-tris(3,3,3-trifluoropropyl)methyl]cyclotrisiloxane-   2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane,-   pentamethylcyclopentasiloxane,-   pentavinylpentamethylcyclopentasiloxane,-   hexamethylcyclotrisiloxane,-   hexaphenylcyclotrisiloxane,-   octamethylcyclotetrasiloxane (OMCTS),-   octaphenylcyclotetrasiloxane,-   decamethylcyclopentasiloxane-   dodecamethylcyclohexasiloxane,-   methyl(3,3,3-trifluoropropl)cyclosiloxane,-   or combinations of any two or more of these.

Another type of precursor starting material, among the preferredstarting materials in the present context, is a polycyclic siloxane, forexample a material having one of the following structural formulas:

in which Y can be oxygen or nitrogen, E is silicon, and Z is a hydrogenatom or an organic substituent, for example alkyl such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others.When each Y is oxygen, the respective structures, from left to right,are a Silatrane, a Silquasilatrane, and a Silproatrane.

Another type of polycyclic siloxane precursor starting material, amongthe preferred starting materials in the present context, is apolysilsesquioxane, with the empirical formula RSiO1.5 and thestructural formula:

in which each R is a hydrogen atom or an organic substituent, forexample alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, vinyl, alkyne, or others. Two commercial materials of this sortare SST-eM01 poly(methylsilsesquioxane), in which each R is methyl, andSST-3MH1.1 poly(Methyl-Hydridosilsesquioxane), in which 90% of the Rgroups are methyl, 10% are hydrogen atoms. This material is available ina 10% solution in tetrahydrofuran, for example. Combinations of two ormore of these are also contemplated. Other examples of a contemplatedprecursor are methylsilatrane, CAS No. 2288-13-3, in which each Y isoxygen and Z is methyl, poly(methylsilsesquioxane) (for example SST-eM01poly(methylsilsesquioxane)), in which each R optionally can be methyl,SST-3MH1.1 poly(Methyl-Hydridosilsesquioxane) (for example SST-3MH1.1poly(Methyl-Hydridosilsesquioxane)), in which 90% of the R groups aremethyl and 10% are hydrogen atoms, or a combination of any two or moreof these.

One particularly contemplated precursor for the barrier coating or layeraccording to the present invention is a linear siloxane, for example isHMDSO. One particularly contemplated precursor for the pH protectivecoating or layer according to the present invention is a cyclicsiloxane, for example octamethylcyclotetrasiloxane (OMCTS).

It is believed that under certain conditions the OMCTS or other cyclicsiloxane molecule provides several advantages over other siloxanematerials. First, its ring structure results in a less dense coating orlayer (as compared to a coating or layer prepared from HMDSO). Themolecule also allows selective ionization so that the final structureand chemical composition of the coating or layer can be directlycontrolled through the application of the plasma power. Otherorganosilicon molecules are readily ionized (fractured) so that it ismore difficult to retain the original structure of the molecule.

Under certain other conditions, acyclic siloxane molecules such as TMDSOor HMDSO can instead be used to provide a suitable tie coating or layer289, barrier coating or layer 288, or pH protective coating or layer286.

Optionally, the PECVD coating or layer can be formed by chemical vapordeposition of a precursor selected from a monocyclic siloxane, apolycyclic siloxane, a polysilsesquioxane, a silatrane, asilquasilatrane, a silproatrane, or a combination of any two or more ofthese precursors.

In any of the PECVD methods according to the present invention, theapplying step optionally can be carried out by vaporizing the precursorand providing it in the vicinity of the substrate. For example, OMCTS isusually vaporized by heating it to about 50° C. before applying it tothe PECVD apparatus.

The reaction gas or precursor can also include a hydrocarbon. Thehydrocarbon can comprise methane, ethane, ethylene, propane, acetylene,or a combination of two or more of these.

The organosilicon precursor can be delivered at a rate of equal to orless than 10 sccm, optionally equal to or less than 6 sccm, optionallyequal to or less than 2.5 sccm, optionally equal to or less than 1.5sccm, optionally equal to or less than 1.25 sccm. Larger pharmaceuticalpackages or other vessels or other changes in conditions or scale mayrequire more or less of the precursor. The precursor can be provided atless than 1 Torr absolute pressure.

Other Components of PECVD Reaction Mixture and Ratios of Components

Generally, for a tie coating or layer 289 or pH protective coating orlayer 286, O₂ can be present in an amount (which can, for example beexpressed by the flow rate in sccm) which is less than, or less than oneorder of magnitude greater than, the organosilicon amount. In contrast,in order to achieve a barrier coating or layer, the amount of O₂typically is at least one order of magnitude higher than the amount oforganosilicon precursor. In particular, the volume ratio (in sccm) oforganosilicon precursor to O₂ for a tie coating or layer 289 or pHprotective coating or layer 286, can be in the range from 0.1:1 to 10:1,optionally in the range from 0.3:1 to 8:1, optionally in the range from0.5:1 to 5:1, optionally from 1:1 to 3:1. The presence of the precursorand O₂ in the volume ratios as given in the working examples isspecifically suitable to achieve a tie coating or layer 289 or pHprotective coating or layer 286. Carrier gas of any embodiment

The tie coating or layer 289 or pH protective coating or layer 286optionally can be made using a carrier gas. The carrier gas,alternatively referred to as a diluent gas since it is not used to takeup or entrain the precursor in the illustrated embodiments, can compriseor consist of an inert gas, for example argon, helium, xenon, neon,another gas that is inert to the other constituents of the process gasunder the deposition conditions, or any combination of two or more ofthese.

In one aspect, a carrier gas is absent in the reaction mixture, inanother aspect, it is present. Suitable carrier gases include Argon,Helium and other noble gases such as Neon and Xenon. When the carriergas is present in the reaction mixture, it is typically present in avolume (in sccm) exceeding the volume of the organosilicon precursor.For example, the ratio of the organosilicon precursor to carrier gas canbe from 1:1 to 1:50, optionally from 1:5 to 1:40, optionally from 1:10to 1:30. One function of the carrier gas is to dilute the reactants inthe plasma, encouraging the formation of a coating on the substrateinstead of powdered reaction products that do not adhere to thesubstrate and are largely removed with the exhaust gases.

Since the addition of Argon gas improves the protective performance (seethe working examples below), it is believed that additional ionizationof the molecule in the presence of Argon contributes to providing a tiecoating or layer 289 or pH protective coating or layer 286. The Si—O—Sibonds of the molecule have a high bond energy followed by the Si—C, withthe C—H bonds being the weakest. A tie coating or layer 289 or pHprotective coating or layer 286, appears to be achieved when a portionof the C—H bonds are broken. This allows the connecting (cross-linking)of the structure as it grows. Addition of oxygen (with the Argon) isunderstood to enhance this process. A small amount of oxygen can alsoprovide C—O bonding to which other molecules can bond. The combinationof breaking C—H bonds and adding oxygen all at low pressure and powerleads to a chemical structure that is solid while providing a tiecoating or layer 289 or pH protective coating or layer 286.

Oxidizing Gas of any Embodiment

The oxidizing gas can comprise or consist of oxygen (O₂ and/or O₃(commonly known as ozone)), nitrous oxide, or any other gas thatoxidizes the precursor during PECVD at the conditions employed. Theoxidizing gas comprises about 1 standard volume of oxygen. The gaseousreactant or process gas can be at least substantially free of nitrogen.

In any of embodiments, one preferred combination of process gasesincludes octamethylcyclotetrasiloxane (OMCTS) or another cyclic siloxaneas the precursor, in the presence of oxygen as an oxidizing gas andargon as a carrier gas. Without being bound to the accuracy of thistheory, the inventors believe this particular combination is effectivefor the following reasons. The presence of O₂, N₂O, or another oxidizinggas and/or of a carrier gas, in particular of a carrier gas, for examplea noble gas, for example Argon (Ar), is contemplated to improve theresulting pH protective coating or layer.

Some non-exhaustive alternative selections and suitable proportions ofthe precursor gas, oxygen, and a carrier gas are provided below.

OMCTS: 0.5-5.0 sccm

Oxygen: 0.1-5.0 sccm

Argon: 1.0-20 sccm

RF Power of any Embodiment

The precursor can be contacted with a plasma made by energizing thevicinity of the precursor with electrodes powered at a frequency of 10kHz to 2.45 GHz, alternatively from about 13 to about 14 MHz.

The precursor can be contacted with a plasma made by energizing thevicinity of the precursor with electrodes powered at radio frequency,optionally at a frequency of from 10 kHz to less than 300 MHz,optionally from 1 to 50 MHz, even optionally from 10 to 15 MHz,optionally at 13.56 MHz.

The precursor can be contacted with a plasma made by energizing thevicinity of the precursor with electrodes supplied with electric powerat from 0.1 to 25 W, optionally from 1 to 22 W, optionally from 1 to 10W, even optionally from 1 to 5 W, optionally from 2 to 4 W, for exampleof 3 W, optionally from 3 to 17 W, even optionally from 5 to 14 W, forexample 6 or 7.5 W, optionally from 7 to 11 W, for example of 8 W, from0.1 to 500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300W, optionally from 1 to 250 W, optionally from 1 to 200 W, evenoptionally from 10 to 150 W, optionally from 20 to 150 W, for example of40 W, optionally from 40 to 150 W, even optionally from 60 to 150 W.

The precursor can be contacted with a plasma made by energizing thevicinity of the precursor with electrodes supplied with electric powerdensity at less than 10 W/ml of plasma volume, alternatively from 6 W/mlto 0.1 W/ml of plasma volume, alternatively from 5 W/ml to 0.1 W/ml ofplasma volume, alternatively from 4 W/ml to 0.1 W/ml of plasma volume,alternatively from 2 W/ml to 0.2 W/ml of plasma volume, alternativelyfrom 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml.

The plasma can be formed by exciting the reaction mixture withelectromagnetic energy, alternatively microwave energy.

Other Process Options of any Embodiment

The applying step for applying a coating or layer to the substrate canbe carried out by vaporizing the precursor and providing it in thevicinity of the substrate.

The chemical vapor deposition employed can be PECVD and the depositiontime can be from 1 to 30 sec, alternatively from 2 to 10 sec,alternatively from 3 to 9 sec. The purposes for optionally limitingdeposition time can be to avoid overheating the substrate, to increasethe rate of production, and to reduce the use of process gas and itsconstituents. The purposes for optionally extending deposition time canbe to provide a thicker coating or layer for particular depositionconditions.

Gaseous Reactant or Process Gas Limitations of any Embodiment

The plasma for PECVD, if used, can be generated at reduced pressure andthe reduced pressure can be less than 300 mTorr, optionally less than200 mTorr, even optionally less than 100 mTorr. The physical andchemical properties of the tie coating or layer 289, the pH protectivecoating or layer 286, or a layer serving the function of more than oneof these can be set by setting the ratio of O2 to the organosiliconprecursor in the gaseous reactant, and/or by setting the electric powerused for generating the plasma.

The plasma of any PECVD embodiment can be formed in the vicinity of thesubstrate. The plasma can in certain cases, especially when preparing abarrier coating or layer, be a non-hollow-cathode plasma. In othercertain cases, especially when preparing the tie coating or layer 289,the pH protective coating or layer 286, or a layer serving the functionof more than one of these a non-hollow-cathode plasma is not desired.The plasma can be formed from the gaseous reactant at reduced pressure.Sufficient plasma generation power input can be provided to inducecoating or layer formation on the substrate.

Relative proportions of gases for producing the tie coating or layer 289or the pH protective coating or layer 286.

The process gas can contain this ratio of gases for preparing the tiecoating or layer 289, the pH protective coating or layer 286, or a layerserving the function of more than one of these:

-   -   from 0.5 to 10 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.1 to 10 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 1 to 80 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 3 to 70 standard volumes, of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   2 to 4 standard volumes, of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes    -   of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 10 to 70 standard volumes, of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 10 to 70 standard volumes, of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   2 to 4 standard volumes, of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        Additional Embodiments

The tie coating or layer 289, the pH protective coating or layer 286, ora layer serving the function of more than one of these described in thisspecification can be applied in many different ways. For one example,the low-pressure PECVD process described in U.S. Pat. No. 7,985,188 canbe used. For another example, instead of using low-pressure PECVD,atmospheric PECVD can be employed to deposit the tie coating or layer289, the pH protective coating or layer 286, or a layer serving thefunction of more than one of these. For another example, the coating canbe simply evaporated and allowed to deposit on the SiOx layer to beprotected. For another example, the coating can be sputtered on the SiOxlayer to be protected.

Process for Applying Tie Coating or Layer 289

The general PECVD process described in this specification is used, forexample as follows, to produce a tie or adhesion coating or layer 289(several names for the same type of coating) on a 1 to 5 mL vessel suchas a pharmaceutical vessel or prefilled syringe. A person skilled in theart will know from this description how to scale the process conditionsto suit larger or smaller vessels.

The tie or adhesion coating or layer can be produced, for example, usingas the precursor tetramethyldisiloxane (TMDSO) or hexamethyldisiloxane(HMDSO) at a flow rate of 0.5 to 10 sccm, preferably 1 to 5 sccm; oxygenflow of 0.25 to 5 sccm, preferably 0.5 to 2.5 sccm; and argon flow of 1to 120 sccm, preferably in the upper part of this range for a 1 mLvessel and the lower part of this range for a 5 ml. vessel. The overallpressure in the vessel during PECVD can be from 0.01 to 10 Torr,preferably from 0.1 to 1.5 Torr. The power level applied can be from 5to 100 Watts, preferably in the upper part of this range for a 1 mLvessel and the lower part of this range for a 5 ml. vessel. Thedeposition time (i.e. “on” time for RF power) is from 0.1 to 10 seconds,preferably 1 to 3 seconds. The power cycle optionally can be ramped orsteadily increased from 0 Watts to full power over a short time period,such as 2 seconds, when the power is turned on, which may improve theplasma uniformity. The ramp up of power over a period of time isoptional, however.

PECVD Process for Applying Barrier Layer

The PECVD processes described as suitable in U.S. Pat. No. 7,985,188,incorporated by reference here, can be used to apply an SiOx barriercoating or layer 288 as defined in this specification.

PECVD Process for pH Protective Layer

A tie coating or layer 289 or a pH protective coating or layer 286 canbe a SiO_(x)C_(y) coating or layer applied as described in anyembodiment of this specification. For example, the pH protective coatingor layer 286 of any embodiment comprises or consists essentially of acoating or layer of SiO_(x)C_(y) optionally applied over the barriercoating or layer 288 to protect at least a portion of the barriercoating or layer from the pharmaceutical preparation such as 218. The pHprotective coating or layer such as 286 is provided, for example, byapplying one of the described precursors on or in the vicinity of asubstrate in a PECVD process, providing a pH protective coating orlayer. The coating can be applied, for example, at a thickness of 1 to5000 nm, or 10 to 1000 nm, or 10 to 500 nm, or 10 to 200 nm, or 20 to100 nm, or 30 to 1000 nm, or 30 to 500 nm thick, or 30 to 1000 nm, or 20to 100 nm, or 80 to 150 nm, and crosslinking or polymerizing (or both)the protective layer, optionally in a PECVD process, to provide aprotected surface.

Although not intending to be bound according to the accuracy of thefollowing theory, the inventors contemplate that the pH protectivecoating or layer 286, applied over an SiO_(x) barrier layer on a vesselwall, functions at least in part by passivating the SiO_(x) barrierlayer surface against attack by the contents of the vessel, as well asproviding a more resistant or sacrificial independent layer to isolatethe SiO_(x) barrier layer from the contents of the vessel. It is thuscontemplated that the pH protective coating or layer can be very thin,and even so improve the shelf life of the pharmaceutical package.

Exemplary reaction conditions for preparing a pH protective coating orlayer 286 coating or layer according to the present invention in a 3 mlsample size vessel with a ⅛″ diameter tube (open at the end) are asfollows:

Flow Rate Ranges:

OMCTS: 0.5-10 sccm

Oxygen: 0.1-10 sccm

Argon: 1.0-200 sccm

Power: 0.1-500 watts

Specific Flow Rates:

OMCTS: 2.0 sccm

Oxygen: 0.7 sccm

Argon: 7.0 sccm

Power: 3.5 watts

The pH protective coating or layer 286 and its application are describedin more detail below. A method for applying the coating includes severalsteps. A vessel wall is provided, as is a reaction mixture comprisingplasma forming gas, i.e. an organosilicon compound gas, optionally anoxidizing gas, and optionally a hydrocarbon gas.

Plasma is formed in the reaction mixture that is substantially free ofhollow cathode plasma. The vessel wall is contacted with the reactionmixture, and the coating or layer of SiOx is deposited on at least aportion of the vessel wall.

It has been found that acyclic organosiloxanes, for example HMDSO andTMDSO, can be used to form the pH protective coating or layer, asdescribed elsewhere in this specification.

In certain embodiments, the generation of a uniform plasma throughoutthe portion of the vessel to be coated is contemplated, as it has beenfound in certain instances to generate a better coating or layer.Uniform plasma means regular plasma that does not include a substantialamount of hollow cathode plasma (which has a higher emission intensitythan regular plasma and is manifested as a localized area of higherintensity interrupting the more uniform intensity of the regularplasma).

Additional Embodiments

The pH protective coating or layer 286 described in this specificationcan be applied in many different ways. For one example, the low-pressurePECVD process described in U.S. Pat. No. 7,985,188 can be used. Foranother example, instead of using low-pressure PECVD, atmospheric PECVDcan be employed to deposit the pH protective coating or layer. Foranother example, the coating can be simply evaporated and allowed todeposit on the SiOx layer to be protected. For another example, thecoating can be sputtered on the SiOx layer to be protected. For stillanother example, the pH protective coating or layer 286 can be appliedfrom a liquid medium used to rinse or wash the SiOx layer.

Other precursors and methods can be used to apply the pH protectivecoating or layer or passivating treatment. For example, hexamethylenedisilazane (HMDZ) can be used as the precursor. HMDZ has the advantageof containing no oxygen in its molecular structure. This passivationtreatment is contemplated to be a surface treatment of the SiOx barrierlayer with HMDZ. To slow down and/or eliminate the decomposition of thesilicon dioxide coatings at silanol bonding sites, the coating must bepassivated. It is contemplated that passivation of the surface with HMDZ(and optionally application of a few mono layers of the HMDZ-derivedcoating) will result in a toughening of the surface against dissolution,resulting in reduced decomposition. It is contemplated that HMDZ willreact with the —OH sites that are present in the silicon dioxidecoating, resulting in the evolution of NH3 and bonding of S—(CH3)3 tothe silicon (it is contemplated that hydrogen atoms will be evolved andbond with nitrogen from the HMDZ to produce NH3).

It is contemplated that this HMDZ passivation can be accomplishedthrough several possible paths.

One contemplated path is dehydration/vaporization of the HMDZ at ambienttemperature. First, an SiOx surface is deposited, for example usinghexamethylene disiloxane (HMDSO). The as-coated silicon dioxide surfaceis then reacted with HMDZ vapor. In an embodiment, as soon as the SiOxsurface is deposited onto the article of interest, the vacuum ismaintained. The HMDSO and oxygen are pumped away and a base vacuum isachieved. Once base vacuum is achieved, HMDZ vapor is flowed over thesurface of the silicon dioxide (as coated on the part of interest) atpressures from the mTorr range to many Torr. The HMDZ is then pumpedaway (with the resulting NH3 that is a byproduct of the reaction). Theamount of NH₃ in the gas stream can be monitored (with a residual gasanalyzer—RGA—as an example) and when there is no more NH₃ detected, thereaction is complete. The part is then vented to atmosphere (with aclean dry gas or nitrogen). The resulting surface is then found to havebeen passivated. It is contemplated that this method optionally can beaccomplished without forming a plasma.

Alternatively, after formation of the SiOx barrier coating or layer, thevacuum can be broken before dehydration/vaporization of the HMDZ.Dehydration/vaporization of the HMDZ can then be carried out in eitherthe same apparatus used for formation of the SiOx barrier coating orlayer or different apparatus.

Dehydration/vaporization of HMDZ at an elevated temperature is alsocontemplated. The above process can alternatively be carried out at anelevated temperature exceeding room temperature up to about 150° C. Themaximum temperature is determined by the material from which the coatedpart is constructed. An upper temperature should be selected that willnot distort or otherwise damage the part being coated.

Dehydration/vaporization of HMDZ with a plasma assist is alsocontemplated. After carrying out any of the above embodiments ofdehydration/vaporization, once the HMDZ vapor is admitted into the part,a plasma is generated. The plasma power can range from a few watts to100+ watts (similar powers as used to deposit the SiOx). The above isnot limited to HMDZ and could be applicable to any molecule that willreact with hydrogen, for example any of the nitrogen-containingprecursors described in this specification.

For depositing a pH protective coating or layer, a precursor feed orprocess gas can be employed having a standard volume ratio of, forexample:

from 0.5 to 10 standard volumes, optionally from 1 to 6 standardvolumes, optionally from 2 to 4 standard volumes, optionally equal to orless than 6 standard volumes, optionally equal to or less than 2.5standard volumes, optionally equal to or less than 1.5 standard volumes,optionally equal to or less than 1.25 standard volumes of the precursor,for example OMCTS or one of the other precursors of any embodiment;

from 0 to 100 standard volumes, optionally from 1 to 80 standardvolumes, optionally from 5 to 100 standard volumes, optionally from 10to 70 standard volumes, of a carrier gas of any embodiment;

from 0.1 to 10 standard volumes, optionally from 0.1 to 2 standardvolumes, optionally from 0.2 to 1.5 standard volumes, optionally from0.2 to 1 standard volumes, optionally from 0.5 to 1.5 standard volumes,optionally from 0.8 to 1.2 standard volumes of an oxidizing agent.

Another embodiment is a pH protective coating or layer of the type madeby the above process.

Another embodiment is a vessel such as the vessel 214 (FIG. 1) includinga lumen defined by a surface defining a substrate. A pH protectivecoating or layer is present on at least a portion of the substrate,typically deposited over an SiO_(x) barrier layer to protect the barrierlayer from dissolution. The pH protective coating or layer is made bythe previously defined process.

PECVD Process for Trilayer Coating

The PECVD trilayer coating described in this specification can beapplied, for example, as follows for a 1 to 5 mL vessel. Two specificexamples are 1 mL thermoplastic resin vessel and a 5 mL thermoplasticresin drug vessel. Larger or smaller vessels will call for adjustmentsin parameters that a person of ordinary skill can carry out in view ofthe teaching of this specification.

The apparatus used is the PECVD apparatus with rotating quadrupolemagnets as described generally in this specification.

The general coating parameter ranges, with preferred ranges inparentheses, for a trilayer coating for a 1 mL vessel are shown in thePECVD Trilayer Process General Parameters Tables (1 mL vessel and 5 mLvessel).

PECVD Trilayer Process General Parameters Table (1 mL vessel) ParameterUnits Tie Barrier pH Protective Power W 40-90 140 40-90 (60-80) (60-80)TMDSO Flow sccm  1-10 None  1-10 (3-5) (3-5) HMDSO Flow sccm None 1.56None O₂ Flow sccm 0.5-5   20 0.5-5   (1.5-2.5) (1.5-2.5) Argon Flow sccm 40-120 0  40-120 (70-90) (70-90) Ramp Time seconds None None NoneDeposition seconds 0.1-10  20 0.1-40  Time (1-3) (15-25) Tube PressureTorr 0.01-10   0.59 0.01-10   (0.1-1.5) (0.1-1.5)

PECVD Trilayer Process General Parameters Table (5 mL vessel) ParameterUnits Adhesion Barrier Protection Power W 40-90 140 40-90 (60-80)(60-80) TMDSO sccm  1-10 None  1-10 Flow (3-5) (3-5) HMDSO sccm None1.56 None Flow O₂ Flow sccm 0.5-5   20 0.5-5   (1.5-2.5) (1.5-2.5) ArgonFlow sccm  40-120 0  40-120 (70-90) (70-90) Ramp Time seconds None NoneNone Deposition seconds 0.1-10  20 0.1-40  Time (1-3) (15-25) Tube Torr0.01-10   0.59 0.01-10   Pressure (0.1-1.5) (0.1-1.5)Trilayer Working Examples

Examples of specific coating parameters that have been used for a 1 mLvessel and 5 mL vessel are shown in the PECVD Trilayer Process SpecificParameters Tables (1 mL vessel and 5 mL vessel):

PECVD Trilayer Process Specific Parameters Table (1 mL syringe)Parameter Units Tie Barrier Protection Power W 70 140 70 TMDSO sccm 4None 4 Flow HMDSO sccm None 1.56 None Flow O₂ Flow sccm 2 20 2 ArgonFlow sccm 80 0 80 Ramp Time seconds None None None Deposition seconds2.5 20 10 Time Tube Torr 1 0.59 1 Pressure

PECVD Trilayer Process Specific Parameters Table (5 mL vessel) ParameterUnits Adhesion Barrier Protection Power W 20 40 20 TMDSO sccm 2 0 2 FlowHMDSO sccm 0 3 0 Flow O₂ Flow sccm 1 50 1 Argon Flow sccm 20 0 20 RampTime seconds 0 2 2 Deposition seconds 2.5 10 10 Time Tube Torr 0.85 1.290.85 Pressure

The O-parameter and N-parameter values for the pH protective coating orlayer applied to the 1 mL vessel as described above are 0.34 and 0.55,respectively.

The O-parameter and N-parameter values for the pH protective coating orlayer applied to the 5 mL vessel are 0.24 and 0.63, respectively.

Referring to FIGS. 16-18, the thickness uniformity at four differentpoints along the length of a 1 mL vessel with a staked needle as thevessel (present during PECVD deposition) and the indicated trilayercoating (avg. thicknesses: 38 nm adhesion or tie coating or layer; 55 nmbarrier coating or layer, 273 nm pH protective coating or layer) isshown. The plot maps the coating thickness over the cylindrical innersurface of the barrel, as though unrolled to form a rectangle. Theoverall range is 572 plus or minus 89 nm. The table shows individuallayer thicknesses at the four marked points, showing adequate thicknessof each layer at each point along the high profile vessel.

A vessel having a coating similar to the trilayer coating of FIG. 18 istested for shelf life, using the silicon dissolution and extrapolationmethod described in this specification, compared to vessels having abilayer coating (similar to the trilayer coating except lacking the tiecoating or layer) and a monolayer coating which is just the pHprotective coating or layer directly applied to the thermoplastic barrelof the vessel, with no barrier layer. The test solution was a 0.2%Tween, pH 8 phosphate buffer. The extrapolated shelf lives of themonolayer and trilayer coatings were similar and very long—on the orderof 14 years. The shelf life of the vessels having a bilayer coating weremuch lower—less than two years. In other words, the presence of abarrier layer under the pH protective layer shortened the shelf life ofthe coating substantially, but the shelf life was restored by providinga tie coating or layer under the barrier layer, sandwiching the barriercoating or layer with respective SiOxCy layers. The barrier layer isnecessary to establish a gas barrier, so the monolayer coating would notbe expected to provide adequate gas barrier properties by itself. Thus,only the trilayer coating had the combination of gas barrier propertiesand a long shelf life, even while in contact with a solution that wouldattack an exposed barrier coating or layer.

FIGS. 19-20 show the coating distribution for a 5 mL vessel—a vialsimilar to that of FIG. 21—showing very little variation in coatingthickness, with the great majority of the surface coated between 150 and250 nm thickness of the trilayer, with only a small proportion of thecontainer coated with between 50 and 250 nm of the trilayer.

The Vessel Coating Distribution Table shows the breakdown of coatingthickness (nm) by vessel location as shown in FIG. 21. The VesselCoating Distribution Table shows the uniformity of coating.

Vessel Coating Distribution Table Vessel Total Trilayer, LocationAdhesion Barrier Protection nm 1 13 29 77 119 2 14 21 58 93 3 25 37 115177 4 35 49 158 242 5 39 49 161 249 6 33 45 148 226 7 31 29 153 213 8 4816 218 282 9 33 53 155 241 10  31 29 150 210 Average 30 36 139 205

FIG. 22 is a visual test result showing the integrity of the trilayervessel coating described above. The three 5 mL cyclic olefin polymer(COC) vessels of FIG. 22 were respectively:

-   -   uncoated (left vessel),    -   coated with the bilayer coating described in this specification        (a barrier coating or layer plus a pH protective coating or        layer—the second and third components of the trilayer coating)        (center vessel); and    -   coated with the trilayer coating as described above (right        vessel).

The three vessels were each exposed to 1 N potassium hydroxide for fourhours, then exposed for 24 hours to a ruthenium oxide (RuO4) stain thatdarkens any exposed part of the thermoplastic vessel unprotected by thecoatings. The high pH potassium hydroxide exposure erodes any exposedpart of the barrier coating or layer at a substantial rate, greatlyreduced, however by an intact pH protective coating or layer. Inparticular, the high pH exposure opens up any pinholes in the coatingsystem. As FIG. 22 shows, the uncoated vessel is completely black,showing the absence of any effective coating. The bilayer coating(Center, FIG. 22, portion enlarged in FIG. 22A) was mostly intact underthe treatment conditions, but on microscopic inspection has manypinholes where the ruthenium stain reached the thermoplastic substratethrough the coating. The overall appearance of the bilayer coatingclearly shows visible “soiled” areas where the stain penetrated. Thetrilayer coating, however (FIG. 22, Right), protected the entire vesselagainst penetration of the stain, and the illustrated vessel remainsclear after treatment. This is believed to be the result of sandwichingthe barrier coating or layer between two layers of SiOxCy, which bothprotects the barrier layer against direct etching and againstundercutting and removal of flakes of the barrier layer.

The rate of erosion of the pH protective coating or layer 286, ifdirectly contacted by the fluid 218, is less than the rate of erosion ofthe barrier coating 288, if directly contacted by the fluid 218.

The pH protective coating or layer 286 is effective to isolate the fluid218 from the barrier coating 288.

Optionally for any of the embodiments, at least a portion of the wall214 of the vessel 250 comprises or consists essentially of a polymer,for example a polyolefin (for example a cyclic olefin polymer, a cyclicolefin copolymer

Optionally for any of the embodiments, the fluid 218 in the lumen suchas 212 or 274 has a pH between 5 and 6, optionally between 6 and 7,optionally between 7 and 8, optionally between 8 and 9, optionallybetween 6.5 and 7.5, optionally between 7.5 and 8.5, optionally between8.5 and 9.

Optionally for any of the embodiments, the fluid 218 is a liquid at 20°C. and ambient pressure at sea level, which is defined as a pressure of760 mm Hg.

Optionally for any of the embodiments, the fluid 218 is an aqueousliquid.

Optionally for any of the embodiments, the barrier coating 288 is from 4nm to 500 nm thick, optionally from 7 nm to 400 nm thick, optionallyfrom 10 nm to 300 nm thick, optionally from 20 nm to 200 nm thick,optionally from 30 nm to 100 nm thick.

Optionally for any of the embodiments, the pH protective coating orlayer 286 comprises or consists essentially of SiO_(x)C_(y). Optionallyfor any of the embodiments, the pH protective coating or layer 286comprises or consists essentially of SiN_(x)C_(y).

Optionally for any of the embodiments, the precursor comprises amonocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, amonocyclic silazane, a polycyclic silazane, a polysilsesquiazane, asilatrane, a silquasilatrane, a silproatrane, an azasilatrane, anazasilquasiatrane, an azasilproatrane, or a combination of any two ormore of these precursors.

Optionally for any of the embodiments, the precursor comprises amonocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, aSilatrane, a Silquasilatrane, a Silproatrane, or a combination of anytwo or more of these precursors. Optionally for any of the embodiments,the precursor comprises octamethylcyclotetrasiloxane (OMCTS) or consistsessentially of OMCTS. Other precursors described elsewhere in thisspecification or known in the art are also contemplated for useaccording to the invention.

Optionally for any of the embodiments, the pH protective coating orlayer 286 as applied is between 10 and 1000 nm thick, optionally between50 and 800 nm thick, optionally between 100 and 700 nm thick, optionallybetween 300 and 600 nm thick. The thickness does not need to be uniformthroughout the vessel, and will typically vary from the preferred valuesin portions of a vessel.

Optionally for any of the embodiments, the pH protective coating orlayer 286 contacting the fluid 218 is between 10 and 1000 nm thick,optionally between 50 and 500 nm thick, optionally between 100 and 400nm thick, optionally between 150 and 300 nm thick two years after thepharmaceutical package 210 is assembled.

Optionally for any of the embodiments, the rate of erosion of the pHprotective coating or layer 286, if directly contacted by a fluid 218having a pH of 8, is less than 20%, optionally less than 15%, optionallyless than 10%, optionally less than 7%, optionally from 5% to 20%,optionally 5% to 15%, optionally 5% to 10%, optionally 5% to 7%, of therate of erosion of the barrier coating 288, if directly contacted by thesame fluid 218 under the same conditions.

Optionally for any of the embodiments, the pH protective coating orlayer 286 is at least coextensive with the barrier coating 288. The pHprotective coating or layer 286 alternatively can be less extensive thanthe barrier coating, as when the fluid does not contact or seldom is incontact with certain parts of the barrier coating absent the pHprotective coating or layer. The pH protective coating or layer 286alternatively can be more extensive than the barrier coating, as it cancover areas that are not provided with a barrier coating.

Optionally for any of the embodiments, the pharmaceutical package 210can have a shelf life, after the pharmaceutical package 210 isassembled, of at least one year, alternatively at least two years.

Optionally for any of the embodiments, the shelf life is measured at 3°C., alternatively at 4° C. or higher, alternatively at 20° C. or higher,alternatively at 23° C., alternatively at 40° C.

Optionally for any of the embodiments, the pH of the fluid 218 isbetween 5 and 6 and the thickness by TEM of the pH protective coating orlayer 286 is at least 80 nm at the end of the shelf life. Alternatively,the pH of the fluid 218 is between 6 and 7 and the thickness by TEM ofthe pH protective coating or layer 286 is at least 80 nm at the end ofthe shelf life. Alternatively, the pH of the fluid 218 is between 7 and8 and the thickness by TEM of the pH protective coating or layer 286 isat least 80 nm at the end of the shelf life. Alternatively, the pH ofthe fluid 218 is between 8 and 9 and the thickness by TEM of the pHprotective coating or layer 286 is at least 80 nm at the end of theshelf life. Alternatively, the pH of the fluid 218 is between 5 and 6and the thickness by TEM of the pH protective coating or layer 286 is atleast 150 nm at the end of the shelf life. Alternatively, the pH of thefluid 218 is between 6 and 7 and the thickness by TEM of the pHprotective coating or layer 286 is at least 150 nm at the end of theshelf life. Alternatively, the pH of the fluid 218 is between 7 and 8and the thickness by TEM of the pH protective coating or layer 286 is atleast 150 nm at the end of the shelf life. Alternatively, the pH of thefluid 218 is between 8 and 9 and the thickness by TEM of the pHprotective coating or layer 286 is at least 150 nm at the end of theshelf life.

Optionally for any of the embodiments, the fluid 218 removes the pHprotective coating or layer 286 at a rate of 1 nm or less of pHprotective coating or layer thickness per 44 hours of contact with thefluid 218 (200 nm per year), alternatively 1 nm or less of pH protectivecoating or layer thickness per 88 hours of contact with the fluid 218(100 nm per year), alternatively 1 nm or less of pH protective coatingor layer thickness per 175 hours of contact with the fluid 218 (50 nmper year), alternatively 1 nm or less of pH protective coating or layerthickness per 250 hours of contact with the fluid 218 (35 nm per year),alternatively 1 nm or less of pH protective coating or layer thicknessper 350 hours of contact with the fluid 218 (25 nm per year). The rateof removing the pH protective coating or layer can be determined by TEMfrom samples exposed to the fluid for known periods.

Optionally for any of the embodiments, the pH protective coating orlayer 286 is effective to provide a lower frictional resistance than theuncoated article surface 254. Preferably the frictional resistance isreduced by at least 25%, more preferably by at least 45%, even morepreferably by at least 60% in comparison to the uncoated article surface254. For example, the pH protective coating or layer 286 preferably iseffective to reduce the frictional resistance between a portion of thewall 214 contacted by the fluid 218 and a relatively sliding part 258after the pharmaceutical package 210 is assembled. Preferably, the pHprotective coating or layer 286 is effective to reduce the frictionalresistance between the wall 214 and a relatively sliding part 258 atleast two years after the pharmaceutical package 210 is assembled.

Optionally, in any embodiment the calculated shelf life of the package(total Si/Si dissolution rate) is more than six months, or more than 1year, or more than 18 months, or more than 2 years, or more than 2½years, or more than 3 years, or more than 4 years, or more than 5 years,or more than 10 years, or more than 20 years. Optionally, in anyembodiment the calculated shelf life of the package (total Si/Sidissolution rate) is less than 60 years.

Any minimum time stated here can be combined with any maximum timestated here, as an alternative embodiment.

Even another embodiment is a medical or diagnostic kit including avessel having a coating or layer as defined in any embodiment herein ona substrate as defined in any embodiment above. Optionally, the kitadditionally includes a medicament or diagnostic agent which iscontained in the vessel in contact with the coating or layer; and/or ahypodermic needle, double-ended needle, or other delivery conduit;and/or an instruction sheet.

The substrate can be a pharmaceutical package or other vessel, forprotecting a compound or composition contained or received in the vesselwith a coating or layer against mechanical and/or chemical effects ofthe surface of the uncoated substrate.

The substrate can be a pharmaceutical package or other vessel, forpreventing or reducing precipitation and/or clotting of a compound or acomponent of the composition in contact with the inner or interiorsurface of the vessel. The compound or composition can be a biologicallyactive compound or composition, for example a medicament, for examplethe compound or composition can comprise insulin, wherein insulinprecipitation can be reduced or prevented. Alternatively, the compoundor composition can be a biological fluid, for example a bodily fluid,for example blood or a blood fraction wherein blood clotting can bereduced or prevented.

A concern of converting from glass to plastic vessels centers around thepotential for leachable materials from plastics. With plasma coatingtechnology, the coatings or layers derived from non-metal gaseousprecursors, for example HMDSO or OMCTS or other organosilicon compounds,will itself contain no trace metals and function as a barrier toinorganic, metals and organic solutes, preventing leaching of thesespecies from the coated substrate into vessel fluids. In addition toleaching control of plastic vessels, the same plasma coating or layertechnology offers potential to provide a solute barrier to the plungertip, typically made of elastomeric plastic compositions containing evenhigher levels of leachable organic oligomers and catalysts.

Moreover, a critical factor in the conversion from glass to plasticvessels will be the improvement of plastic oxygen and moisture barrierperformance. The plasma coating technology is suitable to maintain theSiO_(x) barrier coating or layer for protection against oxygen andmoisture over an extended shelf life.

Substrate

Vessels Generally

A vessel with a coating or layer as described herein and/or preparedaccording to a method described herein can be used for reception and/orstorage and/or delivery of a compound or composition. The compound orcomposition can be sensitive, for example air-sensitive,oxygen-sensitive, sensitive to humidity and/or sensitive to mechanicalinfluences. It can be a biologically active compound or composition, forexample a pharmaceutical preparation or medicament like insulin or acomposition comprising insulin. In another aspect, it can be abiological fluid, optionally a bodily fluid, for example blood or ablood fraction. In certain aspects of the present invention, thecompound or composition can be a product to be administrated to asubject in need thereof, for example a product to be injected, likeblood (as in transfusion of blood from a donor to a recipient orreintroduction of blood from a patient back to the patient) or insulin.

A vessel as described herein and/or prepared according to a methoddescribed herein can further be used for protecting a compound orcomposition contained in its interior space against mechanical and/orchemical effects of the surface of the vessel material. For example, itcan be used for preventing or reducing precipitation and/or clotting orplatelet activation of the compound or a component of the composition,for example insulin precipitation or blood clotting or plateletactivation.

It can further be used for protecting a compound or compositioncontained in its interior against the environment outside of the vessel,for example by preventing or reducing the entry of one or more compoundsfrom the environment surrounding the vessel into the interior space ofthe vessel. Such environmental compound can be a gas or liquid, forexample an atmospheric gas or liquid containing oxygen, air, and/orwater vapor.

A vessel with a trilayer coating as described herein can also beevacuated and stored in an evacuated state. For example, the trilayercoating or layer allows better maintenance of the vacuum in comparisonto a corresponding vessel without a trilayer coating or layer. In oneaspect of this embodiment, the vessel with a trilayer coating or layeris a blood collection tube. The tube can also contain an agent forpreventing blood clotting or platelet activation, for example EDTA orheparin.

Basic Protocols for Forming and Coating Vessels

The vessels tested in the subsequent working examples were formed andcoated according to the following exemplary protocols, except asotherwise indicated in individual examples. Particular parameter valuesgiven in the following basic protocols, for example the electric powerand gaseous reactant or process gas flow, are typical values. Whenparameter values were changed in comparison to these typical values,this will be indicated in the subsequent working examples. The sameapplies to the type and composition of the gaseous reactant or processgas.

In some instances, the reference characters and Figures mentioned in thefollowing protocols and additional details can be found in U.S. Pat. No.7,985,188.

Protocol for Coating Vessel Interior with SiO_(x)

The apparatus and protocol generally as found in U.S. Pat. No. 7,985,188were used for coating vessel interiors with an SiO_(x) barrier coatingor layer, in some cases with minor variations. A similar apparatus andprotocol were used for coating vessels with an SiO_(x) barrier coatingor layer, in some cases with minor variations. Protocol for CoatingVessel Interior with OMCTS pH Protective Coating or Layer

Vessels already interior coated with a barrier coating or layer ofSiO_(x), as previously identified, are further interior coated with a pHprotective coating or layer as previously identified, generallyfollowing the protocols of U.S. Pat. No. 7,985,188 for applying thelubricity coating or layer, except with modified conditions in certaininstances as noted in the working examples. The conditions given hereare for a COC vessel, and can be modified as appropriate for vesselsmade of other materials. The apparatus as generally shown in FIGS. 3 and4 of U.S. Pat. No. 7,985,188 is used to hold a vessel with butt sealingat the base of the vessel. Additionally a cap is provided that seals theend of the vessel (illustrated in present FIG. 3).

The vessel is carefully moved into the sealing position over theextended probe or counter electrode 108 of U.S. Pat. No. 7,985,188 andpushed against a plasma screen. The plasma screen is fit snugly aroundthe probe or counter electrode 108 insuring good electrical contact. Theprobe or counter electrode 108 is grounded to the casing of the RFmatching network.

The gas delivery port 110 of U.S. Pat. No. 7,985,188 is connected to amanual ball valve or similar apparatus for venting, a thermocouplepressure gauge and a bypass valve connected to the vacuum pumping line.In addition, the gas system is connected to the gas delivery port 110allowing the gaseous reactant or process gas,octamethylcyclotetrasiloxane (OMCTS) (or the specific gaseous reactantor process gas reported for a particular example) to be flowed throughthe gas delivery port 110 (under process pressures) into the interior ofthe vessel.

The gas system is comprised of a commercially available heated mass flowvaporization system that heats the OMCTS to about 100° C. The heatedmass flow vaporization system is connected to liquidoctamethylcyclotetrasiloxane (Alfa Aesar® Part Number A12540, 98%). TheOMCTS flow rate is set to the specific organosilicon precursor flowreported for a particular example. To ensure no condensation of thevaporized OMCTS flow past this point, the gas stream is diverted to thepumping line when it is not flowing into the interior of the COC vesselfor processing.

Once the vessel is installed, the vacuum pump valve is opened to thevessel holder 50 and the interior of the COC vessel of U.S. Pat. No.7,985,188. A vacuum pump and blower comprise the vacuum pump system. Thepumping system allows the interior of the COC vessel to be reduced topressure(s) of less than 100 mTorr while the gaseous reactant or processgases is flowing at the indicated rates.

Once the base vacuum level is achieved, the vessel holder 50 assembly ismoved into the electrode 160 assembly. The gas stream (OMCTS vapor) isflowed into the gas delivery port 110 (by adjusting the 3-way valve fromthe pumping line to the gas delivery port 110. Pressure inside the COCvessel is approximately 140 mTorr as measured by a capacitance manometer(MKS) installed on the pumping line near the valve that controls thevacuum. In addition to the COC vessel pressure, the pressure inside thegas delivery port 110 and gas system is also measured with thethermocouple vacuum gauge that is connected to the gas system. Thispressure is typically less than 6 Torr.

Once the gas is flowing to the interior of the COC vessel, the RF powersupply is turned on to its fixed power level. A 600 Watt RF power supplyis used (at 13.56 MHz) at a fixed power level indicated in a specificexample. The RF power supply is connected to an auto match which matchesthe complex impedance of the plasma (to be created in the vessel) to theoutput impedance of the RF power supply. The forward power is as statedand the reflected power is 0 Watts so that the stated power is deliveredto the interior of the vessel. The RF power supply is controlled by alaboratory timer and the power on time set to 10 seconds (or a differenttime stated in a given example).

Upon initiation of the RF power, a uniform plasma is established insidethe interior of the vessel. The plasma is maintained for the entirecoating time, until the RF power is terminated by the timer. The plasmaproduces a pH protective coating or layer on the interior of the vessel.

After pH protective coating, the gas flow is diverted back to the vacuumline and the vacuum valve is closed. The vent valve is then opened,returning the interior of the COC vessel to atmospheric pressure(approximately 760 Torr). The treated vessel is then carefully removedfrom the vessel holder 50 assembly (after moving the vessel holder 50assembly out of the electrode 160 assembly).

A similar protocol is used, except using apparatus generally like thatof FIG. 1 of U.S. Pat. No. 7,985,188, for applying a pH protectivecoating or layer to vessels.

Protocol for Total Silicon Measurement

This protocol is used to determine the total amount of silicon coatingspresent on the entire vessel wall. A supply of 0.1 N potassium hydroxide(KOH) aqueous solution is prepared, taking care to avoid contact betweenthe solution or ingredients and glass. The water used is purified water,18 MΩ) quality. A Perkin Elmer Optima Model 7300DV ICP-OES instrument isused for the measurement except as otherwise indicated.

Each device (vessel, such as a vial, syringe, tube, or the like) to betested and its closure (in the case of a vessel) or other closure areweighed empty to 0.001 g, then filled completely with the KOH solution(with no headspace), closed with the closure, and reweighed to 0.001 g.In a digestion step, each vessel is placed in an autoclave oven (liquidcycle) at 121° C. for 1 hour. The digestion step is carried out toquantitatively remove the silicon coatings from the vessel wall into theKOH solution. After this digestion step, the vessels are removed fromthe autoclave oven and allowed to cool to room temperature. The contentsof the vessels are transferred into ICP tubes. The total Siconcentration is run on each solution by ICP/OES following the operatingprocedure for the ICP/OES.

The total Si concentration is reported as parts per billion of Si in theKOH solution. This concentration represents the total amount of siliconcoatings that were on the vessel wall before the digestion step was usedto remove it.

The total Si concentration can also be determined for fewer than all thesilicon layers on the vessel, as when an SiO_(x) barrier layer isapplied, an SiO_(x)C_(y) second layer (for example, a pH protectivecoating or layer) is then applied, and it is desired to know the totalsilicon concentration of just the SiO_(x)C_(y) layer. This determinationis made by preparing two sets of vessels, one set to which only theSiO_(x) layer is applied and the other set to which the same SiO_(x)layer is applied, followed by the SiO_(x)C_(y) layer or other layers ofinterest. The total Si concentration for each set of vessels isdetermined in the same manner as described above. The difference betweenthe two Si concentrations is the total Si concentration of theSiO_(x)C_(y) second layer.

Protocol for Measuring Dissolved Silicon in a Vessel

In some of the working examples, the amount of silicon dissolved fromthe wall of the vessel by a test solution is determined, in parts perbillion (ppb), for example to evaluate the dissolution rate of the testsolution. This determination of dissolved silicon is made by storing thetest solution in a vessel provided with an SiO_(x) and/or SiO_(x)C_(y)coating or layer under test conditions, then removing a sample of thesolution from the vessel and testing the Si concentration of the sample.The test is done in the same manner as the Protocol for Total SiliconMeasurement, except that the digestion step of that protocol is replacedby storage of the test solution in the vessel as described in thisprotocol. The total Si concentration is reported as parts per billion ofSi in the test solution

Protocol for Determining Average Dissolution Rate

The average dissolution rates reported in the working examples aredetermined as follows. A series of test vessels having a known totalsilicon measurement are filled with the desired test solution analogousto the manner of filling the vessels with the KOH solution in theProtocol for Total Silicon Measurement. (The test solution can be aphysiologically inactive test solution as employed in the presentworking examples or a physiologically active pharmaceutical preparationintended to be stored in the vessels to form a pharmaceutical package).The test solution is stored in respective vessels for several differentamounts of time, then analyzed for the Si concentration in parts perbillion in the test solution for each storage time. The respectivestorage times and Si concentrations are then plotted. The plots arestudied to find a series of substantially linear points having thesteepest slope.

The plot of dissolution amount (ppb Si) versus days decreases in slopewith time, even though it does not appear that the Si layer has beenfully digested by the test solution.

For the PC194 test data in Table 10 below, linear plots of dissolutionversus time data are prepared by using a least squares linear regressionprogram to find a linear plot corresponding to the first five datapoints of each of the experimental plots. The slope of each linear plotis then determined and reported as representing the average dissolutionrate applicable to the test, measured in parts per billion of Sidissolved in the test solution per unit of time.

Protocol for Determining Calculated Shelf Life

The calculated shelf life values reported in the working examples beloware determined by extrapolation of the total silicon measurements andaverage dissolution rates, respectively determined as described in theProtocol for Total Silicon Measurement and the Protocol for DeterminingAverage Dissolution Rate. The assumption is made that under theindicated storage conditions the SiO_(x)C_(y) pH protective coating orlayer will be removed at the average dissolution rate until the coatingis entirely removed. Thus, the total silicon measurement for the vessel,divided by the dissolution rate, gives the period of time required forthe test solution to totally dissolve the SiO_(x)C_(y) coating. Thisperiod of time is reported as the calculated shelf life. Unlikecommercial shelf life calculations, no safety factor is calculated.Instead, the calculated shelf life is the calculated time to failure.

It should be understood that because the plot of ppb Si versus hoursdecreases in slope with time, an extrapolation from relatively shortmeasurement times to relatively long calculated shelf lives is believedto be a “worst case” test that tends to underestimate the calculatedshelf life actually obtainable.

Test Methods

Barrier Improvement Factor

The barrier improvement factor (BIF) of a barrier coating or layer canbe determined by providing two groups of identical containers, adding abarrier layer to one group of containers, testing a barrier property(such as the rate of outgassing in micrograms per minute or anothersuitable measure) on containers having a barrier, doing the same test oncontainers lacking a barrier, and taking a ratio of the properties ofthe materials with versus without a barrier. For example, if the rate ofoutgassing through the barrier is one-third the rate of outgassingwithout a barrier, the barrier has a BIF of 3.

Measurement of Coating Thickness

The thickness of a PECVD coating or layer such as the pH protectivecoating or layer, the barrier coating or layer, the lubricity coating orlayer, and/or a composite of any two or more of these layers can bemeasured, for example, by transmission electron microscopy (TEM). Anexemplary TEM image for a pH protective coating or layer is shown inFIG. 18. An exemplary TEM image for an SiO_(x) barrier coating or layeralso is shown in FIG. 18.

The TEM can be carried out, for example, as follows. Samples can beprepared for Focused Ion Beam (FIB) cross-sectioning in two ways. Eitherthe samples can be first coated with a thin layer of carbon (50-100 nmthick) and then coated with a sputtered coating or layer of platinum(50-100 nm thick) using a K575X Emitech primer coating or layer system,or the samples can be coated directly with the protective sputtered Ptlayer. The coated samples can be placed in an FEI FIB200 FIB system. Anadditional coating or layer of platinum can be FIB-deposited byinjection of an organometallic gas while rastering the 30 kV gallium ionbeam over the area of interest. The area of interest for each sample canbe chosen to be a location half way down the length of the vessel. Thincross sections measuring approximately 15 μm (“micrometers”) long, 2 μmwide and 15 μm deep can be extracted from the die surface using anin-situ FIB lift-out technique. The cross sections can be attached to a200 mesh copper TEM grid using FIB-deposited platinum. One or twowindows in each section, measuring about 8 μm wide, can be thinned toelectron transparency using the gallium ion beam of the FEI FIB.

Cross-sectional image analysis of the prepared samples can be performedutilizing either a Transmission Electron Microscope (TEM), or a ScanningTransmission Electron Microscope (STEM), or both. All imaging data canbe recorded digitally. For STEM imaging, the grid with the thinned foilscan be transferred to a Hitachi HD2300 dedicated STEM. Scanningtransmitted electron images can be acquired at appropriatemagnifications in atomic number contrast mode (ZC) and transmittedelectron mode (TE). The following instrument settings can be used.

Scanning Transmission Electron Instrument Microscope Manufacturer/ModelHitachi HD2300 Accelerating Voltage 200 kV Objective Aperture 2Condenser Lens 1 Setting 1.672 Condenser Lens 2 Setting 1.747Approximate Objective Lens Setting 5.86 ZC Mode Projector Lens 1.149 TEMode Projector Lens 0.7 Image Acquisition Pixel Resolution 1280 × 960Acquisition Time 20 sec.(x4

For TEM analysis the sample grids can be transferred to a Hitachi HF2000transmission electron microscope. Transmitted electron images can beacquired at appropriate magnifications. The relevant instrument settingsused during image acquisition can be those given below.

Instrument Transmission Electron Microscope Manufacturer/Model HitachiHF2000 Accelerating Voltage 200 kV Condenser Lens 1 0.78 Condenser Lens2 0 Objective Lens 6.34 Condenser Lens Aperture 1 Objective LensAperture 3 for imaging Selective Area Aperture N/A for SADSEM Procedure

SEM Sample Preparation: Each vessel sample was cut in half along itslength (to expose the inner or interior surface). The top of the vessel(Luer end) was cut off to make the sample smaller.

The sample was mounted onto the sample holder with conductive graphiteadhesive, then put into a Denton Desk IV SEM Sample Preparation System,and a thin (approximately 50 Å) gold coating was sputtered onto theinner or interior surface of the vessel. The gold coating is used toeliminate charging of the surface during measurement.

The sample was removed from the sputter system and mounted onto thesample stage of a Jeol JSM 6390 SEM (Scanning Electron Microscope). Thesample was pumped down to at least 1×10-6 Torr in the samplecompartment. Once the sample reached the required vacuum level, the slitvalve was opened and the sample was moved into the analysis station.

The sample was imaged at a coarse resolution first, then highermagnification images were accumulated. The SEM images can be, forexample, 5 m edge-to-edge (horizontal and vertical).

XPS

The composition of the SiO_(x) or other barrier coating or layer can bemeasured, for example, by X-ray photoelectron spectroscopy (XPS).

Silicon Dissolution Rate

As shown in the working examples, the silicon dissolution rate ismeasured by determining the total silicon leached from the vessel intoits contents, and does not distinguish between the silicon derived fromthe pH protective coating or layer 286, the barrier coating or layer288, or other materials present.

The invention claimed is:
 1. A blood sample collection tube comprising:a wall having a surface and a coating set on the surface comprising atie coating or layer, a barrier coating or layer, and a pH protectivecoating or layer; the tie coating or layer comprising SiO_(x)C_(y) orSiN_(x)C_(y) wherein x is from about 0.5 to about 2.4 and y is fromabout 0.6 to about 3, the tie coating or layer having an outer surfacefacing the wall surface and the tie coating or layer having an interiorsurface; the barrier coating or layer comprising SiO_(x), wherein x isfrom 1.5 to 2.9, from 2 to 1000 nm thick, the barrier coating or layerof SiO_(x) having an outer surface facing the interior surface of thetie coating or layer and the barrier coating or layer of SiO_(x) havingan interior surface, the barrier coating or layer being effective toreduce the ingress of atmospheric gas through the wall compared to anuncoated wall; and the pH protective coating or layer comprisingSiO_(x)C_(y) or SiN_(x)C_(y) wherein x is from about 0.5 to about 2.4and y is from about 0.6 to about 3, on the barrier coating or layer, thepH protective coating or layer being formed by chemical vapor depositionof a precursor selected from an acyclic siloxane, a monocyclic siloxane,a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, apolycyclic silazane, a polysilsesquiazane, a silatrane, asilquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane,an azasilproatrane, or a combination of any two or more of theseprecursors; and in which the rate of erosion of the pH protectivecoating or layer, if directly contacted by a fluid composition having apH at some point between 5 and 9, is less than the rate of erosion ofthe barrier coating or layer, if directly contacted by the fluidcomposition.
 2. The blood sample collection tube of claim 1, in whichthe pH protective coating or layer as applied is between 100 and 700 nmthick.
 3. The blood sample collection tube of claim 1, in which the rateof erosion of the pH protective coating or layer, if directly contactedby a fluid composition having a pH of 8, is less than 20% of the rate oferosion of the barrier coating or layer, if directly contacted by thesame fluid composition under the same conditions.
 4. The blood samplecollection tube of claim 1, in which the rate of erosion of the pHprotective coating or layer, if directly contacted by a fluidcomposition having a pH of 8, is from 5% to 20% of the rate of erosionof the barrier coating or layer, if directly contacted by the same fluidcomposition under the same conditions.
 5. The blood sample collectiontube of claim 1, in which the silicon dissolution rate by a 50 mMpotassium phosphate buffer diluted in water for injection, adjusted topH 8 with concentrated nitric acid, and containing 0.2 wt. %polysorbate-80 surfactant from the vessel is less than 170 ppb/day. 6.The blood sample collection tube of claim 1, in which x is between 0.5and 1.5 and y is between 0.9 and
 2. 7. The blood sample collection tubeof claim 1, in which the tie coating or layer on average is between 10and 100 nm thick.
 8. The blood sample collection tube of claim 1 inwhich the barrier coating or layer on average is between 10 and 100 nmthick.
 9. The blood sample collection tube of claim 1 in which the rangeof thickness of the pH protective coating or layer is between 50 and 400nm thick.
 10. The blood sample collection tube of claim 1, in which anFTIR absorbance spectrum of the pH protective coating or layer has aratio greater than 0.75 between: the maximum amplitude of the Si—O—Sisymmetrical stretch peak between about 1000 and 1040 cm−1, and themaximum amplitude of the Si—O—Si asymmetric stretch peak between about1060 and about 1100 cm⁻¹.
 11. The blood sample collection tube of claim10, in which the ratio is at most 1.7.
 12. The blood sample collectiontube of claim 1, wherein the pH protective coating or layer shows anO-Parameter measured with attenuated total reflection (ATR) of less than0.4, measured as:${O\text{-}{Parameter}} = {\frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 1253\mspace{14mu}{cm}^{- 1}}{{Maxium}\mspace{14mu}{intensity}\mspace{14mu}{in}\mspace{14mu}{the}\mspace{14mu}{range}\mspace{14mu} 1000\mspace{14mu}{to}\mspace{14mu} 1100\mspace{14mu}{cm}^{- 1}}.}$13. The blood sample collection tube of claim 12, in which theO-parameter has a value of from 0.15 to 0.37.
 14. The blood samplecollection tube of claim 1, wherein the pH protective coating or layershows an N-Parameter measured with attenuated total reflection (ATR) ofless than 0.7, measured as:${N\text{-}{Parameter}} = {\frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 840\mspace{14mu}{cm}^{- 1}}{{Intensity}\mspace{14mu}{at}\mspace{14mu} 799\mspace{14mu}{cm}^{- 1}}.}$15. The blood sample collection tube of claim 14, in which theN-parameter has a value of 0.4 to 0.6.
 16. A blood sample collectiontube comprising: a vessel having a lumen defined at least in part by awall, the wall having an interior surface facing the lumen, an outersurface, and a coating set on the interior surface comprising a tiecoating or layer, a barrier coating or layer, and a pH protectivecoating or layer; the tie coating or layer comprising SiO_(x)C_(y) orSiN_(x)C_(y) wherein x is from about 0.5 to about 2.4 and y is fromabout 0.6 to about 3, the tie coating or layer having an interiorsurface facing the lumen and an outer surface facing the wall interiorsurface; the barrier coating or layer comprising SiO_(x), wherein x isfrom 1.5 to 2.9, from 2 to 1000 nm thick, the barrier coating or layerof SiO_(x) having an interior surface facing the lumen and an outersurface facing the interior surface of the tie coating or layer, thebarrier coating or layer being effective to reduce the ingress ofatmospheric gas into the lumen compared to an vessel without a barriercoating or layer; the pH protective coating or layer comprisingSiO_(x)C_(y) or SiN_(x)C_(y) wherein x is from about 0.5 to about 2.4and y is from about 0.6 to about 3, the pH protective coating or layerhaving an interior surface facing the lumen and an outer surface facingthe interior surface of the barrier coating or layer, the combination ofthe tie coating or layer and the pH protective coating or layer beingeffective to increase the calculated shelf life of the package (totalSi/Si dissolution rate); and a fluid composition contained in the lumenand having a pH between 5 and 9; wherein the calculated shelf life ofthe blood sample collection tube more than six months at a storagetemperature of 4° C.
 17. A blood sample collection tube comprising: athermoplastic wall having an interior surface enclosing a lumen; a fluidcontained in the lumen having a pH greater than 5 disposed in the lumen;a tie coating or layer comprising SiO_(x)C_(y) or SiN_(x)C_(y) wherein xis from about 0.5 to about 2.4 and y is from about 0.6 to about 3, thetie coating or layer having an outer surface facing the wall surface andthe tie coating or layer having an interior surface; a barrier coatingor layer of SiO_(x), in which x is between 1.5 and 2.9, the barriercoating or layer applied by PECVD, positioned between the interiorsurface of the tie coating or layer and the fluid, and supported by thethermoplastic wall, the barrier coating or layer having thecharacteristic of being subject to being measurably diminished inbarrier improvement factor in less than six months as a result of attackby the fluid; and a pH protective coating or layer of SiO_(x)C_(y), inwhich x is between 0.5 and 2.4 and y is between 0.6 and 3, the pHprotective coating or layer applied by PECVD, positioned between thebarrier coating or layer and the fluid and supported by thethermoplastic wall, the pH protective coating or layer and tie coatingor layer together being effective to keep the barrier coating or layerat least substantially undissolved as a result of attack by the fluidfor a period of at least six months.
 18. The blood sample collectiontube of claim 17, in which the fluid composition has a pH between 5 and6.
 19. The blood sample collection tube of claim 17, in which the fluidcomposition has a pH between 6 and
 7. 20. The blood sample collectiontube of claim 17, in which the fluid composition has a pH between 7 and8.
 21. The blood sample collection tube of claim 17, in which the fluidcomposition has a pH between 8 and
 9. 22. The blood sample collectiontube of claim 17, in which the pH protective coating or layer contactingthe fluid composition is between 50 and 500 nm thick two years after theinvention is assembled.
 23. The blood sample collection tube of claim17, in which the calculated shelf life (total Si/Si dissolution rate) ismore than 18 months.
 24. The blood sample collection tube of claim 17,in which the calculated shelf life (total Si/Si dissolution rate) ismore than 2 years.
 25. The blood sample collection tube of claim 17,having a shelf life, after the invention is assembled, of at least twoyears.
 26. The blood sample collection tube of claim 25, in which theshelf life is determined at 20° C.